Neuromodulation cryotherapeutic devices and associated systems and methods

ABSTRACT

Neuromodulation cryotherapeutic devices and associated systems and methods are disclosed herein. A cryotherapeutic device configured in accordance with a particular embodiment of the present technology can include an elongated shaft having distal portion and a supply lumen along at least a portion of the shaft. The shaft can be configured to locate the distal portion intravascularly at a treatment site proximate a renal artery or renal ostium. The supply lumen can be configured to receive a liquid refrigerant. The cryotherapeutic device can further include a cooling assembly at the distal portion of the shaft. The cooling assembly can include an applicator in fluid communication with the supply lumen and configured to deliver cryotherapeutic cooling to nerves proximate the target site when the cooling assembly is in a deployed state.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application claims the benefit of the following applications:

-   -   (a) U.S. Provisional Application No. 61/406,968, filed Oct. 26,        2010;    -   (b) U.S. Provisional Application No. 61/528,091, filed Aug. 26,        2011;    -   (c) U.S. Provisional Application No. 61/528,684, filed Aug. 29,        2011; and    -   (d) U.S. Provisional Application No. 61/546,510, filed Oct. 12,        2011.

All of the foregoing applications are incorporated herein by referencein their entireties. Further, components and features of embodimentsdisclosed in the applications incorporated by reference may be combinedwith various components and features disclosed and claimed in thepresent application.

RELATED APPLICATIONS INCORPORATED BY REFERENCE

U.S. Provisional Application No. 61/545,052, filed Oct. 7, 2011, U.S.patent application Ser. No. 13/204,504, filed Aug. 5, 2011, PCTInternational Application No. PCT/US2011/46845, filed Aug. 5, 2011, andU.S. Provisional Application No. 61/371,110, filed Aug. 5, 2010, arerelated to the present application, and the foregoing applications areincorporated herein by reference in their entireties. As such,components and features of embodiments disclosed in the applicationsincorporated by reference may be combined with various components andfeatures disclosed and claimed in the present application.

TECHNICAL FIELD

The present technology relates generally to cryotherapeutic devices. Inparticular, several embodiments are directed to cryotherapeutic devicesfor intravascular neuromodulation and associated systems and methods.

BACKGROUND

The sympathetic nervous system (SNS) is a primarily involuntary bodilycontrol system typically associated with stress responses. Fibers of theSNS innervate tissue in almost every organ system of the human body andcan affect characteristics such as pupil diameter, gut motility, andurinary output. Such regulation can have adaptive utility in maintaininghomeostasis or in preparing the body for rapid response to environmentalfactors. Chronic activation of the SNS, however, is a common maladaptiveresponse that can drive the progression of many disease states.Excessive activation of the renal SNS in particular has been identifiedexperimentally and in humans as a likely contributor to the complexpathophysiology of hypertension, states of volume overload (such asheart failure), and progressive renal disease. For example, radiotracerdilution has demonstrated increased renal norepinephrine (NE) spilloverrates in patients with essential hypertension.

Cardio-renal sympathetic nerve hyperactivity can be particularlypronounced in patients with heart failure. For example, an exaggeratedNE overflow from the heart and kidneys to plasma is often found in thesepatients. Heightened SNS activation commonly characterizes both chronicand end stage renal disease. In patients with end stage renal disease,NE plasma levels above the median have been demonstrated to bepredictive for cardiovascular diseases and several causes of death. Thisis also true for patients suffering from diabetic or contrastnephropathy. Evidence suggests that sensory afferent signals originatingfrom diseased kidneys are major contributors to initiating andsustaining elevated central sympathetic outflow.

Sympathetic nerves to the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus, and the renal tubules. Stimulation of therenal sympathetic nerves can cause increased renin release, increasedsodium (Na⁺) reabsorption, and a reduction of renal blood flow. Theseneural regulation components of renal function are considerablystimulated in disease states characterized by heightened sympathetictone and likely contribute to increased blood pressure in hypertensivepatients. The reduction of renal blood flow and glomerular filtrationrate as a result of renal sympathetic efferent stimulation is likely acornerstone of the loss of renal function in cardio-renal syndrome(i.e., renal dysfunction as a progressive complication of chronic heartfailure). Pharmacologic strategies to thwart the consequences of renalefferent sympathetic stimulation include centrally acting sympatholyticdrugs, beta blockers (intended to reduce renin release), angiotensinconverting enzyme inhibitors and receptor blockers (intended to blockthe action of angiotensin II and aldosterone activation consequent torenin release), and diuretics (intended to counter the renal sympatheticmediated sodium and water retention). These pharmacologic strategies,however, have significant limitations including limited efficacy,compliance issues, side effects, and others. Accordingly, there is astrong public-health need for alternative treatment strategies.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure. Furthermore,components can be shown as transparent in certain views for clarity ofillustration only and not to indicate that the illustrated component isnecessarily transparent.

FIG. 1 illustrates a cryotherapeutic system in accordance with anembodiment of the present technology.

FIG. 2A is an enlarged cross-sectional view illustrating an embodimentof a distal portion of a shaft and a cooling assembly in a deliverystate (e.g., low-profile or collapsed configuration) in accordance withan embodiment of the present technology.

FIG. 2B is an enlarged cross-sectional view of the cooling assembly ofFIG. 2A in a deployed stated (e.g., expanded configuration).

FIGS. 2C and 2D are enlarged side and end cross-sectional views of acooling assembly configured in accordance with another embodiment of thepresent technology.

FIG. 2E is an enlarged cross-sectional view of proximal and distalportions of a cryotherapeutic device configured in accordance with yetanother embodiment of the present technology.

FIG. 3A illustrates cryogenically modulating renal nerves with acryotherapeutic system in accordance with an embodiment of thetechnology.

FIG. 3B is a block diagram illustrating a method of cryogenicallymodulating renal nerves in accordance with any embodiment of the presenttechnology.

FIGS. 4A and 4B are enlarged cross-sectional views of cryotherapeuticdevices having stepped distal end portions configured in accordance withembodiments of the present technology.

FIG. 5A is a partially schematic view of a cryotherapeutic systemconfigured in accordance with another embodiment of the presenttechnology.

FIG. 5B is an enlarged cross-sectional view of a distal portion of ashaft and a cooling assembly in a deployed state in accordance with anembodiment of the present technology.

FIG. 6A is a plan view illustrating a pre-cooling assembly configured inaccordance with an embodiment of the present technology.

FIG. 6B is a cross-sectional view illustrating the pre-cooling assemblyof FIG. 6A.

FIG. 7 is a cross-sectional view illustrating a pre-cooling assemblyhaving a valve configured in accordance with an embodiment of thepresent technology.

FIG. 8A is a cross-sectional view illustrating a pre-cooling assemblyhaving a flow separator configured in accordance with an embodiment ofthe present technology.

FIG. 8B is a cross-sectional view illustrating the pre-cooling assemblyof FIG. 8A.

FIG. 9A is a cross-sectional view illustrating a pre-cooling assemblyhaving a flow separator configured in accordance with another embodimentof the present technology.

FIG. 9B is a cross-sectional view illustrating the pre-cooling assemblyof FIG. 9A.

FIG. 10 is a partially schematic view illustrating a tubular member of apre-cooling assembly coiled around an exhaust portal within a handleconfigured in accordance with an embodiment of the present technology.

FIG. 11 is a partially schematic view illustrating a tubular member of apre-cooling assembly coiled near an exhaust portal within a handleconfigured in accordance with an embodiment of the present technology.

FIG. 12 is a cross-sectional view illustrating a cooling assembly havingsupply tubes with angled distal portions configured in accordance withan embodiment of the present technology.

FIG. 13 is a cross-sectional view illustrating a cooling assembly havinga supply tube with a helical portion wrapped around an exhaust passageconfigured in accordance with an embodiment of the present technology.

FIG. 14 is a cross-sectional view illustrating a cooling assembly havinga supply tube with a helical portion wrapped around an exhaust passageconfigured in accordance with another embodiment of the presenttechnology.

FIG. 15A is a cross-sectional view illustrating a cooling assemblyhaving an inner balloon with inner-balloon orifices configured inaccordance with an embodiment of the present technology.

FIG. 15B is a cross-sectional view illustrating the cooling assembly ofFIG. 15A.

FIG. 16A is a cross-sectional view illustrating a cooling assemblyhaving an inner balloon with inner-balloon orifices and an outer balloonwith a raised helical portion configured in accordance with anembodiment of the present technology.

FIG. 16B is a cross-sectional view illustrating the cooling assembly ofFIG. 16A.

FIG. 17A is a cross-sectional view illustrating a cooling assemblyhaving elongated, thermally-insulative members configured in accordancewith an embodiment of the present technology.

FIG. 17B is a cross-sectional view illustrating the cooling assembly ofFIG. 17A.

FIG. 18A is a cross-sectional view illustrating a cooling assemblyhaving elongated, thermally-insulative members configured in accordancewith another embodiment of the present technology.

FIG. 18B is a cross-sectional view illustrating the cooling assembly ofFIG. 18A.

FIG. 19A is a profile view illustrating a cooling assembly having ahelical thermally-insulative member configured in accordance with anembodiment of the present technology.

FIGS. 19B and 19C are cross-sectional views illustrating the coolingassembly of FIG. 19A.

FIG. 20A is a profile view illustrating a cooling assembly having athermally-insulative member resembling an intertwined double helixconfigured in accordance with an embodiment of the present technology.

FIGS. 20B and 20C are cross-sectional views illustrating the coolingassembly of FIG. 20A.

FIG. 21A is a cross-sectional view illustrating a cooling assemblyhaving elongated, thermally-insulative members movable within a balloonconfigured in accordance with another embodiment of the presenttechnology.

FIG. 21B is a cross-sectional view illustrating the cooling assembly ofFIG. 21A.

FIG. 21C is a cross-sectional view illustrating the cooling assembly ofFIG. 21A in a delivery state within a delivery sheath.

FIG. 22A is a cross-sectional view illustrating a cooling assemblyhaving elongated, thermally-insulative members movable within a balloonconfigured in accordance with an embodiment of the present technology.

FIG. 22B is a cross-sectional view illustrating the cooling assembly ofFIG. 22A.

FIG. 23A is a profile view illustrating a cooling assembly havingmultiple partially-circumferential balloons configured in accordancewith an embodiment of the present technology.

FIG. 23B is an isometric view illustrating the cooling assembly of FIG.23A.

FIG. 24A is a profile view illustrating a cooling assembly havingmultiple partially-circumferential balloons configured in accordancewith another embodiment of the present technology.

FIG. 24B is an isometric view illustrating the cooling assembly of FIG.24A.

FIG. 25 is a profile view illustrating a cooling assembly having ahelical recess configured in accordance with an embodiment of thepresent technology.

FIG. 26 is a profile view illustrating a cooling assembly having spacedapart recesses configured in accordance with an embodiment of thepresent technology.

FIG. 27A is a profile view illustrating a cooling assembly having spacedapart recesses configured in accordance with another embodiment of thepresent technology.

FIG. 27B is a cross-sectional view illustrating the cooling assembly ofFIG. 27A.

FIG. 27C is an isometric view illustrating the cooling assembly of FIG.27A.

FIG. 28 is a profile view illustrating a cooling assembly having spacedapart protrusions configured in accordance with an embodiment of thepresent technology.

FIG. 29 is a profile view illustrating a cooling assembly having ahelical balloon wrapped around an exhaust passage configured inaccordance with an embodiment of the present technology.

FIG. 30 is a profile view illustrating a cooling assembly having ahelical balloon wrapped around a supply lumen configured in accordancewith an embodiment of the present technology.

FIG. 31 is a profile view illustrating a cooling assembly having ahelical balloon wrapped around a supply lumen configured in accordancewith another embodiment of the present technology.

FIG. 32A is a profile view illustrating a cooling assembly having ashaping member with a shape memory configured in accordance with anembodiment of the present technology.

FIG. 32B is a cross-sectional view illustrating the cooling assembly ofFIG. 32A.

FIG. 33A is a profile view illustrating a cooling assembly having aballoon curved along its length configured in accordance with anembodiment of the present technology.

FIGS. 33B and 33C are cross-sectional views illustrating the coolingassembly of FIG. 33A.

FIG. 33D is a cross-sectional view illustrating the cooling assembly ofFIG. 33A in a delivery state within a delivery sheath.

FIG. 34 is a cross-sectional view illustrating a cooling assembly havinga balloon curved along its length configured in accordance with anotherembodiment of the present technology.

FIG. 35A is a profile view illustrating a cooling assembly having aballoon having a constrained longitudinal portion configured inaccordance with an embodiment of the present technology.

FIG. 35B is a cross-sectional view illustrating the cooling assembly ofFIG. 35A.

FIG. 36 is a cross-sectional view illustrating a cooling assembly havinga balloon having a constrained longitudinal portion configured inaccordance with another embodiment of the present technology.

FIG. 37 is a profile view illustrating a cooling assembly having alooped balloon configured in accordance with an embodiment of thepresent technology.

FIG. 38A is a profile view illustrating a cooling assembly havingmultiple elongated balloons configured in accordance with an embodimentof the present technology.

FIG. 38B is a cross-sectional view illustrating the cooling assembly ofFIG. 38A.

FIG. 39A is a profile view illustrating a cooling assembly havingmultiple elongated balloons configured in accordance with anotherembodiment of the present technology.

FIGS. 39B and 39C are cross-sectional views illustrating the coolingassembly of FIG. 39A.

FIG. 40 is a cross-sectional view illustrating a cooling assembly havingmultiple elongated balloons configured in accordance with anotherembodiment of the present technology.

FIG. 41 is a profile view illustrating a cooling assembly havingmultiple helical balloons configured in accordance with an embodiment ofthe present technology.

FIG. 42 is a profile view illustrating a cooling assembly havingmultiple helical balloons configured in accordance with anotherembodiment of the present technology.

FIG. 43A is a profile view illustrating a cooling assembly havingmultiple elongated balloons attached to a shaping member configured inaccordance with an embodiment of the present technology.

FIG. 43B is a cross-sectional view illustrating the cooling assembly ofFIG. 43A.

FIG. 43C is a profile view illustrating the cooling assembly of FIG. 43Awith the shaping member retracted.

FIG. 44A is a profile view illustrating a cooling assembly havingmultiple elongated balloons attached to a shaping member configured inaccordance with another embodiment of the present technology.

FIG. 44B is a cross-sectional view illustrating the cooling assembly ofFIG. 44A.

FIG. 44C is a profile view illustrating the cooling assembly of FIG. 44Awith the shaping member retracted.

FIG. 45A is a profile view illustrating a cooling assembly havingmultiple elongated balloons of different composition configured inaccordance with an embodiment of the present technology.

FIG. 45B is a cross-sectional view illustrating the cooling assembly ofFIG. 45A expanded to a first cross-sectional dimension.

FIG. 45B-1 is an enlarged cross-sectional view illustrating a partitionshown in FIG. 45B.

FIG. 45C is a cross-sectional view illustrating the cooling assembly ofFIG. 45A expanded to a second cross-sectional dimension, larger than thefirst cross-sectional dimension.

FIG. 46 is a cross-sectional view illustrating a cooling assembly havingmultiple elongated balloons of different composition configured inaccordance with another embodiment of the present technology.

FIG. 46-1 is an enlarged cross-sectional view illustrating a partitionshown in FIG. 46.

FIG. 47 is a profile view illustrating a cooling assembly having ahelical primary balloon wrapped around a secondary balloon configured inaccordance with an embodiment of the present technology.

FIG. 48A is a profile view illustrating a cooling assembly having ahelical primary balloon within a secondary balloon configured inaccordance with an embodiment of the present technology.

FIG. 48B is a cross-sectional view illustrating the cooling assembly ofFIG. 48A.

FIG. 49 is a profile view illustrating a cooling assembly having ahelical primary balloon wrapped around a secondary balloon configured inaccordance with another embodiment of the present technology.

FIG. 50 is a profile view illustrating a cooling assembly having ahelical primary balloon wrapped around a secondary balloon configured inaccordance with another embodiment of the present technology.

FIG. 51 is a profile view illustrating a cooling assembly having ahelical primary balloon wrapped around a secondary balloon configured inaccordance with another embodiment of the present technology.

FIG. 52A is a profile view illustrating a distal portion of acryotherapeutic device including a cooling assembly and an occlusionmember configured in accordance with an embodiment of the presenttechnology.

FIG. 52B is a cross-sectional view illustrating the distal portion ofFIG. 52A.

FIG. 53 is a cross-sectional view illustrating a distal portion of acryotherapeutic device including a cooling assembly and an occlusionmember configured in accordance with another embodiment of the presenttechnology.

FIG. 54 is a cross-sectional view illustrating a cooling assembly thatcan be well-suited for circulation of refrigerant without phase changeconfigured in accordance with an embodiment of the present technology.

FIG. 55 is a cross-sectional view illustrating a cooling assembly thatcan be well-suited for circulation of refrigerant without phase changeconfigured in accordance with another embodiment of the presenttechnology.

FIG. 56 is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

FIG. 57 is an enlarged anatomic view of nerves innervating a left kidneyto form the renal plexus surrounding the left renal artery.

FIGS. 58A and 58B are anatomic and conceptual views, respectively, of ahuman body depicting neural efferent and afferent communication betweenthe brain and kidneys.

FIGS. 59A and 59B are anatomic views of the arterial vasculature andvenous vasculature, respectively, of a human.

DETAILED DESCRIPTION

Specific details of several embodiments of the technology are describedbelow with reference to FIGS. 1-59B. Although many of the embodimentsare described below with respect to devices, systems, and methods forintravascular modulation of renal nerves using cryotherapeuticapproaches, other applications and other embodiments in addition tothose described herein are within the scope of the technology.Additionally, several other embodiments of the technology can havedifferent configurations, components, or procedures than those describedherein. A person of ordinary skill in the art, therefore, willaccordingly understand that the technology can have other embodimentswith additional elements, or the technology can have other embodimentswithout several of the features shown and described below with referenceto FIGS. 1-59B.

With regard to the terms “distal” and “proximal” within thisdescription, unless otherwise specified, the terms can reference arelative position of the portions of a cryotherapeutic device and/or anassociated delivery device with reference to an operator and/or alocation in the vasculature. For example, proximal can refer to aposition closer to the operator of the device or an incision into thevasculature, and distal can refer to a position that is more distantfrom the operator of the device or further from the incision along thevasculature.

Renal Neuromodulation

Renal neuromodulation is the partial or complete incapacitation or othereffective disruption of nerves innervating the kidneys. In particular,renal neuromodulation comprises inhibiting, reducing, and/or blockingneural communication along neural fibers (i.e., efferent and/or afferentnerve fibers) innervating the kidneys. Such incapacitation can belong-term (e.g., permanent or for periods of months, years, or decades)or short-term (e.g., for periods of minutes, hours, days, or weeks).Renal neuromodulation is expected to efficaciously treat severalclinical conditions characterized by increased overall sympatheticactivity, and in particular conditions associated with centralsympathetic overstimulation such as hypertension, heart failure, acutemyocardial infarction, metabolic syndrome, insulin resistance, diabetes,left ventricular hypertrophy, chronic and end stage renal disease,inappropriate fluid retention in heart failure, cardio-renal syndrome,and sudden death. The reduction of afferent neural signals contributesto the systemic reduction of sympathetic tone/drive, and renalneuromodulation is expected to be useful in treating several conditionsassociated with systemic sympathetic overactivity or hyperactivity.Renal neuromodulation can potentially benefit a variety of organs andbodily structures innervated by sympathetic nerves. For example, areduction in central sympathetic drive may reduce insulin resistancethat afflicts patients with metabolic syndrome and Type II diabetics.Additionally, osteoporosis can be sympathetically activated and mightbenefit from the downregulation of sympathetic drive that accompaniesrenal neuromodulation. A more detailed description of pertinent patientanatomy and physiology is provided below.

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the kidneys. Cryotherapy, forexample, includes cooling tissue at a target site in a manner thatmodulates neural function. The mechanisms of cryotherapeutic tissuedamage include, for example, direct cell injury (e.g., necrosis),vascular injury (e.g., starving the cell from nutrients by damagingsupplying blood vessels), and sublethal hypothermia with subsequentapoptosis. Exposure to cryotherapeutic cooling can cause acute celldeath (e.g., immediately after exposure) and/or delayed cell death(e.g., during tissue thawing and subsequent hyperperfusion). Severalembodiments of the present technology include cooling a structure at ornear an inner surface of a renal artery wall such that proximate (e.g.,adjacent) tissue is effectively cooled to a depth where sympatheticrenal nerves reside. For example, the cooling structure is cooled to theextent that it causes therapeutically effective, cryogenic renal-nervemodulation. Sufficiently cooling at least a portion of a sympatheticrenal nerve is expected to slow or potentially block conduction ofneural signals to produce a prolonged or permanent reduction in renalsympathetic activity.

Cryotherapy has certain characteristics that can be beneficial forintravascular renal neuromodulation. For example, rapidly cooling tissueprovides an analgesic effect such that cryotherapies may be less painfulthan ablating tissue at high temperatures. Cryotherapies may thusrequire less analgesic medication to maintain patient comfort during aprocedure compared to heat ablation procedures. Additionally, reducingpain mitigates patient movement and thereby increases operator successand reduces procedural complications. Cryotherapy also typically doesnot cause significant collagen tightening, and thus cryotherapy is nottypically associated with vessel stenosis.

Cryotherapies generally operate at temperatures that causecryotherapeutic applicators to adhere to moist tissue. This can bebeneficial because it promotes stable, consistent, and continued contactduring treatment. The typical conditions of treatment can make this anattractive feature because, for example, a patient can move duringtreatment, a catheter associated with an applicator can move, and/orrespiration can cause the kidneys to rise and fall and thereby move therenal arteries. In addition, blood flow is pulsatile and causes therenal arteries to pulse. Adhesion associated with cryotherapeuticcooling also can be advantageous when treating short renal arteries inwhich stable intravascular positioning can be more difficult to achieve.

Selected Embodiments of Renal Cryogenic Systems

FIG. 1 illustrates a cryotherapeutic system 100 configured in accordancewith several embodiments of the present technology. The cryotherapeuticsystem 100 can include a console 102 and a cryotherapeutic device 120.In the embodiment shown in FIG. 1, the console 102 includes a supplycontainer 104, a refrigerant 106 in the supply container 104, and asupply control valve 108 in fluid communication with the supplycontainer 104. The supply container 104 can be a single-use cartridge ora larger container that contains a sufficient volume of refrigerant 106to perform multiple procedures. The larger supply containers, forexample, can be refillable cylinders. The supply container 104 isconfigured to retain the refrigerant 106 at a desired pressure. Forexample, in one embodiment, liquid N₂O is contained in the supplycontainer 104 at a pressure of 750 psi or greater so it is in at least asubstantially liquid state at ambient temperatures. In otherembodiments, the refrigerant 106 can include carbon dioxide, ahydrofluorocarbon (“HFC”; e.g., Freon®, R-410A, etc.), and/or othersuitable compressed or condensed refrigerants that can be retained inthe supply container 104 at a sufficiently high pressure to maintain therefrigerant 106 in at least a substantially liquid state at ambienttemperatures (e.g., approximately 210 psi for R-410A).

The supply control valve 108 is coupled to a supply line 110 configuredto transport the refrigerant 106 to the cryotherapeutic device 120. Thesupply control valve 108 can be operated manually or automatically. Theconsole 102 can optionally include a pump 111, such as a vacuum pump ora DC power pump, and/or a backpressure control valve 113 coupled to anexhaust line 115 configured to receive exhausted refrigerant 117 fromthe cryotherapeutic device 120. The pump 111 can reduce the backpressureof evaporated refrigerant and, in conjunction with the supply flow rate,increase refrigeration power. In other embodiments, the expandedrefrigerant 117 can exhaust to ambient pressure.

The console 102 can further include an optional controller 118 thatoperates the supply control valve 108 and the backpressure control valve113. The controller 118, for example, can be a processor or dedicatedcircuitry that implements a computerized algorithm for executing aprocedure automatically. The console 102 may also include an optionaluser interface that receives user input and/or provides information tothe user and/or circuitry for monitoring optional sensors (e.g.,pressure or temperature) if present in the cryotherapeutic device 120.In one embodiment, the controller 118 operates the backpressure controlvalve 113 to control the amount of vacuum applied to the exhaustedrefrigerant 117 returning from the cryotherapeutic device 120. Thismodulates the backpressure of the evaporated refrigerant to control thetemperature in the cryotherapeutic device 120. In another embodiment,the supply control valve 108 and/or the backpressure control valve 113can be used to increase the backpressure of exhausted refrigerant 117.Increasing the backpressure of exhausted refrigerant 117 could increasethe boiling point of the refrigerant. For example, in the case of N₂O, aslight increase in backpressure from 1 atm to about 2 atm would raisethe boiling point from about −88° C. to about −75° C.; an increase inbackpressure to 3 atm would raise the boiling point to about −65° C.

In certain embodiments, the cryotherapeutic system 100 may also precoolthe refrigerant 106 to provide greater refrigeration power in therefrigerant 106 by the time it reaches the cooling system. The system100, for example, can include a precooler 119 (shown in dashed lines) inthe console 102. In other embodiments, the system 100 can include aprecooler along the supply line 110, at a handle at a proximal region ofthe system 100, or elsewhere coupled to the cryotherapeutic device 120.

The cryotherapeutic device 120 includes a shaft 122 that has a proximalportion 124, a handle 125 at a proximal region of the proximal portion124, and a distal portion 126 extending distally relative to theproximal portion 124. The cryotherapeutic device 120 can further includea cooling assembly 130 at the distal portion 126 of the shaft 122. Theshaft 122 is configured to locate the distal portion 126 intravascularlyat a treatment site proximate (e.g., in or near) a renal artery or renalostium, and the cooling assembly 130 is configured to providetherapeutically-effective cryogenic renal-nerve modulation.

FIG. 2A is an enlarged cross-sectional view illustrating an embodimentof the distal portion 126 of the shaft 122 and the cooling assembly 130in a delivery state (e.g., low-profile or collapsed configuration), andFIG. 2B is an enlarged cross-sectional view of the cooling assembly 130in a deployed stated (e.g., expanded configuration). In the embodimentshown in FIG. 2A, the distal portion 126 of the shaft 122 can include afirst zone 127 a and a second zone 127 b (separated by broken lines)recessed inwardly relative to the first zone 127 a. The first zone 127 acan be demarcated from the second zone 127 b by a step 128, such as arabbet (e.g., an annular or other circumferential groove configured tobe fitted with another member). The first zone 127 a can accordinglyhave a first outer dimension or first cross-sectional dimension (e.g.,area or diameter), and the second zone 127 b can have a second outerdimension or second cross-sectional dimension less than the firstdimension. The shaft 122 can be sized to fit within a sheath 150 of 8 Fror smaller (e.g., a 6 Fr guide sheath) to accommodate small renalarteries.

The cryotherapeutic device 120 can also include a supply tube or lumen132 and an exhaust tube or lumen 134 along at least a portion of theshaft 122. The supply lumen 132 can be a small tube configured to retainthe refrigerant in a liquid state at a high pressure. The inner diameterof the supply lumen 132 is selected such that at least a portion of therefrigerant reaching the cooling assembly 130 is in a liquid state at adistal end 135 of the supply lumen 132. The exhaust lumen 134 can be anouter tube, and the supply lumen 132 can extend within the exhaust lumen134 along at least the distal portion 126 of the shaft. As described infurther detail below, several embodiments of the cryotherapeutic device120 can further include one or more sensors 138, such as a temperaturesensor or pressure sensor, coupled to the controller 118 (FIG. 1) by alead 139. In several embodiments, the cryotherapeutic system 100 can beconfigured to verify the proper calibration of the sensors 138 before acryotherapeutic treatment. For example, the cryotherapeutic system 100can automatically compare a measured temperature from a temperaturesensor with room temperature as the cryotherapeutic system 100 initiatesa power up cycle to check that the temperature sensor is functioningproperly.

The embodiment of the cooling assembly 130 shown in FIGS. 2A and 2B canhave an applicator 140 including a balloon 142 or other type ofexpandable member that defines an expansion chamber configured to fullyocclude a renal artery or renal ostium. The balloon 142 can berelatively short (e.g., 10 mm or less) to accommodate the length andtortuosity of a renal artery (e.g., between 4-6 cm) and can have adiameter in an expanded configuration large enough to contact asignificant portion of the inner circumference of the renal artery(e.g., between 3-10 mm in diameter). In other embodiments describedbelow, balloons can be configured to only partially occlude a renalartery or renal ostium. The balloon 142 can comprise a compliantmaterial, a non-compliant material, and/or a combination of compliantand non-compliant materials. In various embodiments, for example, theballoon 142 can be made from polyurethane and/or other compliant orsemi-compliant materials that can expand and conform to vessel walls tofully occlude vessels of varying sizes (e.g., vessels having an innerdiameter from approximately 3 mm to approximately 10 mm, or in specificapplications approximately 4 mm to approximately 8 mm). In otherembodiments, the balloon 142 can be made from nylon and/or othernon-compliant materials and sized to accommodate vessels within acertain size range. For example, a non-compliant nylon balloon can besized to accommodate vessels having an inner diameter betweenapproximately 3 mm and 6 mm, and a larger non-compliant nylon ballooncan be sized to accommodate vessels having an inner diameter betweenapproximately 7 mm and 10 mm.

In the embodiment illustrated in FIGS. 2A and 2B, the distal portion ofthe balloon 142 is not connected to a support member (e.g., the supplylumen 132 and/or other support), and can therefore be dip molded and/orotherwise formed to have a continuous distal portion. The continuousdistal portion of the balloon 142 provides a gentle surface with whichto contact vessel walls so as to avoid tearing, puncturing, and/orotherwise damaging vessel walls. Additionally, the cooling assembly 130shown in FIG. 2B can have a shorter overall length than a distallyconnected balloon, which may facilitate positioning the cooling assembly130 in relatively short vessels (e.g., a renal artery having a length of6 cm or less).

The cooling assembly 130 can further include an orifice 144 in fluidcommunication with the expansion chamber. In one embodiment, the orifice144 can be defined by a distal end of a capillary tube 146 inserted intothe distal end 135 of the supply lumen 132. Alternatively, the openingat the distal end 135 of the supply lumen 132 can define an orifice. Thecapillary tube 146 and/or the orifice 144 can have a diameter less thanthat of the supply lumen 132 to impede the flow of refrigerant proximatethe expansion chamber, thereby increasing the pressure drop of therefrigerant 106 entering the expansion chamber and concentrating therefrigeration power at the cooling assembly 130. In other embodiments,the supply lumen 132 may have a substantially constant inner diameter(e.g., 0.008 inch (0.203 mm), 0.009 inch (0.023 mm), 0.010 inch (0.254mm), etc.) such that the orifice 144 has a diameter at least equal tothat of the supply lumen 132. The cryotherapeutic device 120 can thenfurther include additional hardware (e.g., valves, flow and pressuregauges, etc.) and/or software in the handle 125 (FIG. 1) and/or in theconsole 102 (FIG. 1) to control the refrigerant 106 through the supplylumen 132 and focus the refrigeration power toward the distal endportion 126 of the shaft 122.

The orifice 144 can be sized relative to the area and/or length of theexhaust lumen 134 at the distal portion 126 of the shaft 122 to providea sufficient flow rate of refrigerant, produce a sufficient pressuredrop in the expansion chamber, and allow for sufficient venting of theexhausted refrigerant 117 through the exhaust lumen 134. In oneembodiment, the orifice 144 can have a diameter of approximately 0.003inch (0.076 mm) or more, such as about 0.004 inch (0.101 mm) to about0.009 inch (0.229 mm). In various embodiments, the inner diameter and/orcross-sectional area of the exhaust lumen 132 and the diameter and/orcross-sectional area of the orifice 144 can have a ratio betweenapproximately 4:1 and 10:1. For example, the exhaust lumen 132 can havean inner diameter between approximately 0.030 inch (0.762 mm) andapproximately 0.050 inch (1.27 mm), and the orifice 144 can have adiameter of approximately 0.003 inch (0.0762 mm) to approximately 0.008inch (0.203 mm; e.g., 0.004 inch (0.101 mm)). In other embodiments, theexhaust lumen 134 and the orifice 144 can have other suitabledimensions. In further embodiments, the shaft 122 may include additionallumens or devices extending there through (e.g., pressure sensinglumens, additional fluid passageways, etc.) and the ratio of thecross-sectional dimension of the exhaust lumen 132 to the totalcross-sectional dimension occupied by the supply lumen and/or othermembers within the shaft 122 can be approximately 4:1 and 10:1.

The flow rate of the refrigerant 106 can also be manipulated by changingthe lengths of the supply lumen 132 and the capillary tube 146 relativeto one another. For example, in certain embodiments, the capillary tube146 can be at most ⅓ the length of the supply lumen 132. In variousembodiments, the capillary tube 146 can have a length between 2 inches(5.08 cm) and 30 inches (76.2 cm) and the supply lumen 132 can be sizedaccordingly. In other embodiments, the capillary tube 146 can be shorteror longer relative to the supply lumen 132 and/or the capillary tube 146can be omitted.

The cooling assembly 130 is passed intravascularly to a target site T ina vessel V while in the delivery configuration shown in FIG. 2A.Referring to FIG. 2B, the cooling assembly 130 and the sheath 150 arethen moved relative to each other such that the cooling assembly 130extends distally beyond the sheath 150. For example, the sheath 150 canbe pulled proximally and/or the cooling assembly 130 can be pusheddistally. In operation, the refrigerant 106 passes through the supplylumen 132, through the orifice 144, and into the expansion chamberdefined by the balloon 142. As the refrigerant 106 passes through theorifice 144, it expands into a gaseous phase, thereby inflating theballoon and causing a significant temperature drop in the expansionchamber. The portion of the applicator 140 contacting the tissue at thetarget T can be a heat-transfer region 149 or heat-transfer zone that,together with the refrigerant 106 in the expansion chamber, causestherapeutically-effective, cryogenic renal-nerve modulation. Exhaustedrefrigerant 117 passes in a proximal direction through the exhaust lumen134. In various embodiments, the length of shaft 122 can be minimized todecrease the losses (e.g., friction losses) of the refrigerant flowingthrough the supply lumen 132 and through the exhaust lumen 134, therebyenhancing the refrigeration potential and the efficiency of the coolingassembly 130. The additional friction losses that may be caused bylonger exhaust lumens, for example, may inhibit venting of the exhaustedrefrigerant 117, and thereby increase the pressure and temperaturewithin the balloon 142. Accordingly, the shaft 122 can be configured tohave a total overall length of less than 90 cm (e.g., 80 cm to 85 cm, 70cm to 80 cm, etc.). In other embodiments, the shaft 122 can be longerand/or include additional features to enhance the refrigeration power atthe cooling assembly 130.

The embodiment of the cooling assembly 130 illustrated in FIGS. 2A and2B fully occludes the vessel V and produces a full-circumferentialtreatment at the target site T (i.e., a continuous cooled regionextending completely around the inner circumference of the vessel V in aplane that is perpendicular or otherwise transverse relative to alongitudinal direction of the vessel V at the target T). Fully occludingthe vessel V limits blood flow from heating the heat-transfer region 149such that the cooling power of the refrigerant can be more efficientlyapplied to the target T. Although occlusion of the renal blood vesselfor an excessive period of time can potentially cause ischemia of akidney, it has been found that renal blood flow can be fully occludedfor a period of time sufficient to complete cryotherapy at the target T(e.g., 2-5 minutes). The controller 118 (FIG. 1) can be programmed tolimit the duration of refrigerant flow (e.g., 2-5 minutes) by using anelectronic or mechanical timer to control a valve. Alternatively, atimer can be incorporated into the handle 125 (FIG. 1) or other portionof the cryotherapeutic device 120. If present, the sensor 138 mayprovide feedback to the controller 118 to regulate or control the system100. In some embodiments, it may be desirable for the control algorithmto be fully automated, but in other embodiments the delivered therapymay utilize user input. In further embodiments, the duration ofrefrigerant flow can be limited by the volume of the refrigerant in thesupply container 104. As described in greater detail below, in otherembodiments, the cooling assembly 130 can be configured to partiallyocclude blood flow.

In various embodiments, the sensor 138 can be a thermocouple positionedon an outer surface of the balloon 142 and configured to provide areal-time temperature reading of the external temperature of the balloon142. As such, the cryotherapeutic system 100 can be regulated via thecontroller 118 (e.g., using a software control loop) such that it rampsthe cooling power output up and down based on the difference between thereal-time external balloon temperature and a predetermined treatmenttemperature (e.g., −40° C., −60° C., etc.). For example, the coolingpower output can be regulated by switching valves (e.g., the supplycontrol valve 108 and/or the backpressure control valve 113) on and offat various stages of a cryotherapeutic treatment in response to measuredtemperatures. In other embodiments, the cooling power output can bemodulated using proportional control wherein the delivery pressure ofthe refrigerant 106 and/or the flow rate of the vacuum pump 111 can bevaried in response to the measured external balloon temperature.Accordingly, the external thermocouple allows the cryotherapeutic system100 to compensate for variables that affect cooling at the target siteT, such as variations in artery diameter, blood flow through the artery,and/or blood flow through other vessels in the vicinity of the renalartery.

FIGS. 2C-2E are enlarged cross-sectional views illustrating the distalportion 126 of the cryotherapeutic device 120 configured in accordancewith other embodiments of the present technology. Referring to FIG. 2C,a distal portion 152 of the balloon 142 can be connected to a distalconnector 162 via thermal bonding, adhesives, and/or other suitableattachment mechanisms. The distal connector 162 can have a curved,bullet-like tip as shown in FIG. 2C or can be otherwise configured toprovide an atraumatic tip for navigation through the vasculature.

The cryotherapeutic device 120 further includes a guide wire lumen 133 athrough which a guide wire 133 b can be received to guide the distalportion 126 of the shaft 122 through the vasculature. In the embodimentillustrated in FIG. 2C, the guide wire lumen 133 a extends completelythrough the shaft 122 from the proximal opening of the shaft 122 at anadaptor 201 (e.g., at the handle 125 shown in FIG. 1) to beyond thedistal opening of the shaft 122 in an over-the-wire (OTW) configuration,whereas in the embodiment illustrated in FIG. 2E, the guide wire lumen133 a extends through only a portion of the shaft 122 in a rapidexchange (RX) configuration. Although the proximal end of the guide wirelumen 133 a is shown in FIG. 2E extending through the sidewall of theshaft 122 at the distal portion 126, in other embodiments, the proximalend of the guide wire lumen 133 a can be accessible anywhere between theproximal and distal ends of the shaft 122. The guide wire lumen 133 ashown in FIGS. 2C-2E, or variations thereof, may be included in variousembodiments described herein to facilitate navigation through thevasculature. Suitable OTW and RX guide wire configurations are disclosedin U.S. Pat. No. 545,134, filed Oct. 27, 1994, U.S. Pat. No. 5,782,760,filed May 23, 1995, U.S. Patent Publication No. 2003/0040769, filed Aug.23, 2001, and U.S. Patent Publication No. 2008/0171979, filed Oct. 17,2006, each of which is incorporated herein by reference in its entirety.

FIG. 3A illustrates cryogenically modulating renal nerves with anembodiment of the system 100. The cryotherapeutic device 120 providesaccess to the renal plexus through an intravascular path P that leads toa respective renal artery RA. As illustrated, a section of the proximalportion 124 of the shaft 122 is exposed externally of the patient. Bymanipulating the proximal portion 124 of the shaft 122 from outside theintravascular path P, the caregiver may advance the shaft 122 throughthe tortuous intravascular path P (e.g., via the femoral artery or aradial artery) and remotely manipulate the distal portion 126 (e.g.,with an actuator in the handle 125). For example, the shaft 122 mayfurther include one or more pull-wires or other guidance devices todirect the distal portion 126 through the vasculature. Image guidance,e.g., CT, radiographic, IVUS, OCT or another suitable guidance modality,or combinations thereof, may be used to aid the caregiver'smanipulation. After the cooling applicator 140 is adequately positionedin the renal artery RA or at the renal ostium, it can be expanded orotherwise deployed using the console 102 (FIG. 1), the handle 125 (FIG.1), and/or another means until the applicator 140 contacts the innerwall of the renal artery RA. The purposeful application of cooling powerfrom the applicator 140 is then applied to tissue to induce one or moredesired neuromodulating effects on localized regions of the renal arteryand adjacent regions of the renal plexus, which lay intimately within,adjacent to, or in close proximity to the adventitia of the renalartery. The purposeful application of the neuromodulating effects mayachieve neuromodulation along all or a portion of the renal plexus.

The neuromodulating effects are generally a function of, at least inpart, the temperature of the applicator 140, contact between theapplicator 140 and vessel wall, dwell time of the applicator 140 whilecooling, number of cooling cycles (e.g., one or more cooling cyclesseparated by a warming period), and blood flow through the vessel.Desired cooling effects may include cooling the applicator such that thetemperatures of target neural fibers are below a desired threshold toachieve cryo alteration or ablation. For example, the refrigerant gas inthe applicator 140 can be cooled to a temperature of about −88° C. toabout −60° C., or in other embodiments the gas in the applicator 140 canhave a temperature of about −80° C. to about −40° C.

In various embodiments, neuromodulating effects can occur within 100seconds (e.g., 90 seconds, 75 seconds, 60 seconds, 30 seconds, etc.) ofapplying the cooled applicator 140 to the renal artery RA or renalostium in one or more cooling cycles. In one embodiment, the process caninclude two cooling cycles separated by a warming period, but in otherembodiments the process can have more than two cooling cycles separatedby warming periods. The cooling cycles can have the same duration ordifferent durations, such as approximately 10 seconds to approximately90 seconds each. The duration(s) of the warming periods can besufficient to partially or completely thaw frozen matter at the coolinginterface. In several embodiments, the duration(s) of the warmingperiods can be from about 5 seconds to about 90 seconds. Individualwarming periods between cooling cycles may last for the same amount oftime or for different amounts of time. The durations of the cooling andwarming cycles can be predetermined and programmed into an algorithm, orthe system can include an automatic control algorithm using a feedbackloop based on the pressure and/or temperature within and/or on theexternal surface of the balloon. For example, the control algorithm canterminate a warming cycle and initiate a cooling cycle by assessing whenthe frozen matter has sufficiently thawed based on the pressure and/ortemperature measurements. Depending upon the number and length ofcooling cycles, the total procedure time from the deployment of thecooling assembly 130 (e.g., as shown in FIG. 2B) to retraction of thecooling assembly to the delivery state (e.g., as shown in FIG. 2A) canbe less than five minutes (e.g., less than 3 minutes). When both renalarteries RA are treated, the total procedure time from the time ofdeployment of the cooling assembly 130 in the first renal artery RA, torepositioning, deployment, and retraction of the cooling assembly 130 inthe second renal artery RA can be less than 12 minutes (e.g., 10minutes, 6 minutes, etc.). In certain embodiments, the procedure timecan be decreased by locating the applicator 140 around a fullcircumference of the renal artery RA (e.g., along the same plane oralong parallel planes spaced laterally apart) and performingneuromodulation in a single application. In other embodiments, theapplicator 140 can be applied to less than a full circumference of therenal artery RA and/or in more than one application.

FIG. 3B is a block diagram illustrating a method 300 of cryogenicallymodulating renal nerves using the system 100 described above withreference to FIGS. 1-3A or another suitable system in accordance with anembodiment of the present technology described below. Referring to FIGS.1-3B together, the method 300 can include intravascularly locating thecooling assembly 130 in the delivery state (e.g., as shown in FIG. 2A)in a renal artery or renal ostium (block 305). The cryotherapeuticdevice 120 and/or portions thereof (e.g., the cooling assembly 130) canbe inserted into a guide catheter (e.g., the sheath 150 shown in FIGS.2A-2C) to facilitate intravascular delivery of the cooling assembly 130.In certain embodiments, for example, the cryotherapeutic device 120 canbe configured to fit within an 8 Fr guide catheter or smaller (e.g., 7Fr, 6 Fr, etc.) to access small peripheral vessels. As described above,an OTW or RX guide wire can also be used to manipulate and enhancecontrol of the shaft 122 and the cooling assembly 130.

The method 300 can further include connecting the cryotherapeutic device120 to the console 102 (block 310), and partially or fully inflating anexpandable member of the cooling assembly 130 (e.g., the balloon 142) todetermine whether the cooling assembly 130 is in the correct position atthe target site (blocks 315 and 320). The expandable member can beinflated via the supply lumen 132 with refrigerant from the supplycontainer 104 at the console 102 and/or with other suitable fluids(e.g., air) from a secondary fluid supply reservoir in fluidcommunication the expandable member. If the cooling assembly 130 is notin the desired location, at least some of the pressure in the expandablemember can be released (block 325). In certain embodiments, for example,the expandable member can be fully deflated by disconnecting thecryotherapeutic device 120 from the console 102 and using a syringe tomanually deflate the expandable member via a proximal end portion of theshaft 122. In other embodiments, the cryotherapeutic device 120 canremain attached to the console 102, and a syringe can be connected alongthe length of the shaft 122 (e.g., a stopcock syringe) to deflate theexpandable member. In further embodiments, the controller 118 at theconsole 102 can include algorithms for partially or fully deflating theexpandable member. In still further embodiments, the cooling assembly130 can be positioned at the target site using radiopaque markers and/ormarkings.

Once the cooling assembly 130 is properly located within the first renalartery or ostium thereof, the console 102 can be manipulated to initiatecooling at the cooling assembly 130 that modulates the renal nerves tocause partial or full denervation of the kidney (block 330). Cryogeniccooling can be applied for one or more cycles (e.g., for 30 secondincrements, 60 second increments, 90 second increments, etc.) in one ormore locations along the circumference and/or length of the first renalartery or first renal ostium. In one particular embodiment, for example,two 90 second cycles may be used. In various embodiments, the expandablemember can remain fully or partially inflated to maintain the positionof the cooling assembly 130 at the target site between cooling cycles.

After renal-neuromodulation at the first renal artery, the method 300can further include deflating the expandable member and retracting thecooling assembly 130 into the delivery state (block 335). The expandablemember can be deflated manually by detaching the cryotherapeutic device120 from the console 102 and connecting a syringe or other suitableevacuation device to the proximal end of the shaft 122. In otherembodiments, a syringe can be connected along the length of the shaft122 without detaching the cryotherapeutic device 120 from the console102, or the expandable member can be deflated automatically (e.g., viathe controller 118). In certain embodiments, the cooling assembly 130can be withdrawn back into the guide catheter after the expandablemember is deflated. Optionally, the cooling assembly 130 can be removedfrom the guide catheter during repositioning and temporarily stored in asterile location (e.g., in a saline solution).

The cooling assembly 130 can then be located in a second renal artery orsecond renal ostium (block 340), and the expandable member can beexpanded to confirm the position of the cooling assembly 130 (block345). In selected embodiments, a contrast material can be delivereddistally beyond the cooling assembly 130 and fluoroscopy and/or othersuitable imaging techniques can be used to locate the second renalartery. If necessary, the used supply container 104 in the console 102can be refilled or removed and replaced with a new supply container(e.g., a disposable refrigerant cartridge) to provide sufficientrefrigerant for renal-neuromodulation at the second renal artery orsecond renal ostium. In embodiments where the console 102 was detachedfrom the cryotherapeutic device 120 during repositioning of the coolingassembly 130, the console 102 can be reconnected to the cryotherapeuticdevice 120 such that the method 300 continues by applying cryogeniccooling to effectuate renal-neuromodulation at the second renal arteryor second renal ostium (block 350).

In other embodiments, various steps in the method 300 can be modified,omitted, and/or additional steps may be added. For example, the console102 can be turned on and loaded with the supply container 104 outsidethe sterile field in which the cryotherapy occurs, and positioned in asterile bag or housing such that it can be brought into the sterilefield. If the supply container 104 must be reloaded or refilled duringcryotherapy, the console 102 can be removed from the sterile field,reloaded, and placed back into the sterile field (e.g., in a sterile bagor housing). In other embodiments, the empty supply container 104 can beremoved from the console 102 and deposited within a sterile bag orhousing surrounding the console 102, and a new supply container can beattached to the console 102 within the sterile bag or housing such thatthe console 102 does not leave the sterile field during treatment. Infurther embodiments, the console 102 can remain outside the sterilefield and operated remotely.

FIG. 4A is an enlarged cross-sectional view of a distal portion 426 of acryotherapeutic device 420 configured in accordance with anotherembodiment of the present technology. The cryotherapeutic device 420includes features generally similar to the features of thecryotherapeutic device 120 described above with reference to FIGS. 1-3B.For example, the cryotherapeutic device 420 includes the elongated shaft122, the supply and exhaust lumens 132 and 134 extending along at leasta portion of the shaft 122, and the cooling assembly 130 at the distalportion 426 of the shaft 102. The cooling assembly 130 includes anexpandable member, such as the balloon 142 or other suitable expandablemember, that defines at least a portion of the expansion chamber andreceives the refrigerant 106 in an at least substantially gas phase viathe orifice 144.

In the illustrated embodiment, the distal end 135 of the supply lumen132 is coupled to a distal portion 452 of the balloon 142 to provideadditional support and/or control for the cooling assembly 130, and theorifice 144 is an opening positioned along the length of the supplylumen 132 (e.g., rather than at the distal end 135 of the supply lumen132 or at the end of a capillary tube). The supply lumen 132 and thedistal portion 452 of the balloon 142 can be attached together usingadhesives (e.g., thermal bonds), fasteners, and/or other suitableattachment mechanisms known in the art. In other embodiments, the supplylumen 132 can terminate at or in the expansion chamber, and/or thecryotherapeutic device 420 can further include a support member (notshown) that extends from the shaft 122 to at least the distal portion452 of the balloon 142.

As shown in FIG. 4A, the cryotherapeutic device 420 can further includea connector 454 at the proximal portion of the balloon 142 that can beattached over the distal portion 426 of the shaft 122 and thereby couplethe balloon 142 to the shaft 122. The connector 454 can be defined by aproximal portion of the balloon 142 (e.g., the neck of the balloon 142)that is integral with the expandable portion as shown in FIG. 4A, or theconnector 454 can be a separate and distinct component from the balloon142, such as a collar or other suitable retainer. The connector 454 canbe attached to the distal portion 426 of the shaft 122 using thermalbonds, adhesives, interlocking surfaces (e.g., threads), friction fit,snap fit, suction, and/or other suitable attachment mechanisms, or theconnector 454 can be formed integrally with the distal portion 426.

In the illustrated embodiment, the connector 454 is positioned proximatethe step 128 over the second zone 127 b of the distal portion 426 of theshaft 122. As shown in FIG. 4A, the first zone 127 a of the distalportion 426 can have a first outer cross-sectional dimension or diameterOD₁ and the second zone 127 b distal to the step 128 can have a secondouter cross-sectional dimension or diameter OD₂ less than the firstouter cross-sectional dimension OD₁. The reduction in the outerdimension of the distal portion 426 at the step 128 forms an inwardrecess relative to the first zone 127 a in which at least a portion ofthe connector 454 and the proximal region of the expandable portion ofthe balloon 142 can sit, and thereby reduces the profile of the distalportion 426 of the shaft 122. In certain embodiments, the step 128 canbe dimensioned such that an outer surface 455 of the first zone 127 a isat least substantially flush with an outer surface 457 of the connector454. Accordingly, the outer diameter OD₂ of the second zone 127 b can beequivalent to the outer diameter OD₁ of the first zone 127 a less twicethe thickness of the connector 454. In other embodiments, the outerdiameter OD₂ of the second zone 127 b can be greater than or less thantwice the thickness of the connector 454.

In selected embodiments, the connector 454 is non-expandable such thatit remains within the recess and/or substantially flush with the outersurface 455 of the first zone 127 a when the cooling assembly 130 movesto the deployed state (e.g., as shown in FIG. 4A). In other embodiments,the connector 454 may be expandable and increase in cross-sectional areaas the cooling assembly 130 moves to the deployed state.

In the embodiment shown in FIG. 4A, the cross-sectional area of theexhaust lumen (e.g., defined by the inner surface(s) of the shaft 122)also decreases at the transition between the first zone 127 a and thesecond zone 127 b such that the distal portion 426 of the shaft 122 hasa first inner cross-sectional dimension or diameter ID₁ at the firstzone 127 a and a lesser second inner cross-sectional dimension ordiameter ID₂ at the second zone 127 b. To avoid a build up of pressurein the expansion chamber that may be caused by insufficient ventingthrough the necked-down exhaust lumen 134, the second zone 127 b can bepositioned only at the distal-most end of the shaft 122 proximate theexpansion chamber where the density of the exhausted refrigerant 117 isthe highest. For example, the second zone 127 b can have a length ofless than 4 cm (e.g., 2 cm, 1 cm, etc.). The exhausted refrigerant 117also vents adequately through the smaller inner diameter ID₂ of thesecond zone 127 b without undue restriction because the length of thesecond zone 127 b along the longitudinal axis of the shaft 122 can berelatively short. For example, the length of the second zone 127 b canbe minimized to sufficiently accommodate the connector 454. Accordingly,the smaller exhaust lumen 134 at the second zone 127 b can transportprimarily high density exhausted refrigerant 117 and can expel theexhausted refrigerant 117 into the larger exhaust lumen 134 at the firstzone 127 a as the exhausted refrigerant 117 decreases in density,thereby facilitating adequate venting through the smaller second innerdiameter ID₂ of the second zone 127 b.

In operation, the inwardly recessed second zone 127 b can reduce theprofile of the distal portion 426 of the shaft 122 and/or provide asubstantially smooth transition from the shaft 122 to the connector 454without jeopardizing the venting characteristics of the exhaust lumen134. The low-profile distal portion 426 of the shaft 122 can alsofacilitate the delivery of a fluidic contrast material between the shaft122 and the sheath 150 from the proximal portion 124 (FIG. 1) of theshaft 122 to the distal portion 426 and around the cooling assembly 130in the delivery state (e.g., as shown in FIG. 2A) to image and locate(e.g., using fluoroscopy) a target in the vasculature. As shown in FIG.4A, for example, the recessed second zone 127 b provides one or morepassageways or channels C around the distal portion 426 of the shaft 122that are large enough to deliver contrast material distally beyond thecooling assembly 130 without being blocked by a protruding connector orballoon. In certain embodiments, a sufficient channel C for the contrastmaterial can be formed when the difference between the first outerdiameter OD₁ and the second outer diameter OD₂ of the correspondingfirst and second zones 127 a and 127 b is less than 0.01 inch (0.254mm). In other embodiments, the difference between the outer dimensionsCID₁ and OD₂ of the first and second zones 127 a and 127 b may begreater or smaller. When used during renal-neuromodulation, a firstrenal artery can be located by delivering contrast material distallybeyond the cooling assembly 130 in the delivery state via the channel C.After renal-neuromodulation at the first renal artery, the coolingassembly 130 can be retracted back from the deployed state to thedelivery state wherein additional contrast material can be delivereddistally beyond the cooling assembly 130 via the channel C to locate asecond renal artery.

In other embodiments, the distal portion 426 of the shaft 122 does notinclude the stepped-down exhaust lumen 134 shown in FIG. 4A and,instead, may have a substantially uniform cross-sectional dimension.Such an exhaust lumen may relatively easily accommodate a guide wirelumen (e.g., as shown in FIGS. 2C-2E) through which a guide wire can beextended to locate the cooling assembly 130 at the target site T in thevessel V. In this embodiment, contrast material for imaging target sites(e.g., two renal arteries) can be delivered distally via the guide wirelumen after the guide wire has been retracted.

FIG. 4B is an enlarged cross-sectional view of a distal portion 456 of acryotherapeutic device 460 configured in accordance with anotherembodiment of the present technology. The cryotherapeutic device 460includes features generally similar to the features of thecryotherapeutic device 420 described above with reference to FIG. 4A.For example, the distal portion 456 of the shaft 122 has the step 128that demarcates the first zone 127 a from the smaller second zone 127 b.However, in the embodiment shown in FIG. 4B, the second zone 127 b isdefined by a separate tube 459 that protrudes from the shaft 122. Thetube 459 decreases the cross-sectional area of the exhaust lumen 134 atthe second zone 127 b similar to the inwardly stepped portion of theshaft 122 shown in FIG. 4A.

As shown in FIG. 4B, the cryotherapeutic device 460 can further includea proximal connector 458 that attaches the balloon 142 to the distalportion 456 of the shaft 122. Unlike the connector 456 of FIG. 4A thatsits substantially within the recess formed by the step 128, theproximal connector 458 shown in FIG. 4B extends over the second zone 127b onto the outer surface 455 of the first zone 127 a. By extending theproximal connector 456 over the first zone 127 a, a larger surface areais made available for attaching the balloon 142 to the distal portion456 of the shaft 122. Accordingly, the length of the second zone 127 bcan be reduced to facilitate adequate venting of the refrigerant 117through the necked-down exhaust lumen 134 (e.g., as shown in FIGS. 4Aand 4B).

In certain embodiments, the proximal connector 458 is non-expandablesuch that it maintains a substantially low profile against the outersurface 455 of the first zone 127 a in both the deployed and deliverystates. This can reduce or prevent the proximal connector 458 fromcatching on the sheath 150 as it is retracted from the deployed to thedelivery configuration. In other embodiments, at least a portion of theproximal connector 458 can be expandable, but configured to maintain thelow profile of the distal portion 456 while the cooling assembly 130 isin the delivery state. Accordingly, the cryotherapeutic device 460 withthe extended proximal connector 458 can provide a substantially lowprofile for intravascularly delivering the cooling assembly 130 at atarget site within a small, peripheral vessel (e.g., a renal artery)and/or can provide one or more channels C through which a fluidiccontrast material can be delivered distally beyond the cooling assembly130.

As further shown in FIG. 4B, the cryotherapeutic device 460 alsoincludes a distal connector 462 that retains the distal portion 452 ofthe balloon 142 and a support member 433 extending through the balloon142 that braces the balloon 142 in both the delivery and deployedstates. The distal connector 462 can also be attached to (e.g., bythermal bonding) or formed integrally with an atraumatic tip 464 thatextends distally therefrom. The atraumatic tip 464 can extendapproximately 0.5 cm to 5 cm (e.g., approximately 1-2 cm) from thedistal connector 462 and have an outer diameter between approximately0.010 inch (0.254 mm) to approximately 0.050 inch (1.27 mm). In oneembodiment, for example, the atraumatic tip 464 can have a length ofapproximately 2 cm and an outer diameter of at least 0.035 inch (0.889mm; e.g., 0.038 inch (0.965 mm)). In other embodiments, the atraumatictip 464 can have other suitable lengths and/or outer diameters. Theatraumatic tip 464 can serve as a fixed guide to facilitate navigationthrough the vasculature. In several embodiments, the angle and/orrotational orientation of the atraumatic tip 464 can be adjusted by acontrol wire 467 (e.g., a pull-wire) that extends through at least aportion of the shaft 122. A user can manipulate the control wire 467 totortionally deflect or otherwise move the atraumatic tip 464 to steerthe distal portion 456 of the shaft 122 to the target site T. In otherembodiments, the atraumatic tip 464 can be defined by a distal endportion of a guide wire (e.g., the guide wire 133 b shown in FIG. 2C)that extends through the shaft 122 and beyond the distal connector 462.

The atraumatic tip 464 can be made from substantially smooth andflexible materials or structures such that it can gently contact anddeflect off of vessel walls as the cryotherapeutic device 460 navigatesthe vasculature, and therefore avoids perforation and/or other trauma tothe vessels through which it navigates. For example, the atraumatic tip464 can be made from a flexible coil (e.g., a platinum coil) over a coreor wire (e.g., a stainless steel wire). In various embodiments, the wirecan be configured to gradually taper from a proximal portion 469 a ofthe atraumatic tip 464 to a distal portion 469 b of the atraumatic tip464. A tapered wire, for example, can be generally round at the proximalportion 469 a having an outer diameter between approximately 0.005 inch(0.127 mm) and 0.015 inch (0.381 mm; e.g., 0.009 inch (0.229 mm)) andcan flatten toward the distal portion 469 b to a thickness betweenapproximately 0.001 inch (0.025 mm) and approximately 0.005 inch (0.127mm; e.g., 0.003 inch (0.076 mm)). In selected embodiments, the wire issubstantially flat by about ⅓ to ½ of the length of the atraumatic tip464 from the proximal terminus. In other embodiments, the atraumatic tip464 can have a tapered or non-tapered generally circular cross-sectionthroughout. In several embodiments, at least a portion of the atraumatictip 464 (e.g., a coil wrapped around the wire) can be made from platinumand/or other radiopaque materials (e.g., a platinum/iridium alloy) thatcan facilitate navigation of the cryotherapeutic device 460 through thevasculature using imaging techniques known in the art. In certainaspects of the technology, the balloon 142 can also include radiopaquemarkers and/or radiopaque markings (e.g., made with radiopaque ink) atboth its proximal and distal end portions to further facilitatenavigation and deployment. In other embodiments, the atraumatic tip 464can be made from other deflectable and gentle materials and structures,such as a polymer material (e.g., Pebax® polymer, nylon, etc.), apolymer material over a metallic wire (e.g., a stainless steel wire),and/or other suitable materials.

In the embodiment illustrated in FIG. 4B, the atraumatic tip 464 isshaped and/or otherwise formed into a curve or angled portion. When theatraumatic tip 464 is made from a shapeable material (e.g., stainlesssteel, platinum, etc.), the atraumatic tip 464 can be formed and/orreformed into the desired curvature. In other embodiments, theatraumatic tip 464 can be pre-formed from a non-shapeable material suchthat it has a non-adjustable, set curve. The curve in the atraumatic tip464 can further aid in navigation of the vasculature. For example, thecurve can aid in keeping the cooling assembly 130 within a desiredvessel (e.g., a renal artery) and avoiding side braches thereof.

Pressure Monitoring in Cryotherapeutic Systems

FIG. 5A is a partially schematic view of a cryotherapeutic system 500configured in accordance with another embodiment of the presenttechnology, and FIG. 5B is an enlarged cross-sectional view of a distalend portion of the system 500 of FIG. 5A. The cryotherapeutic system 500can include features generally similar to the features of thecryotherapeutic system 100 described above with reference to FIGS. 1-3B.Referring to FIG. 5A, for example, the cryotherapeutic system 500 caninclude a cryotherapeutic device 520 and a console 502. The console 502can include a refrigerant supply container 504 and a supply controlvalve 508 that are coupled to a supply line 510 configured to transportthe refrigerant 506 to the cryotherapeutic device 520. The console 502can also optionally include a pump 511 and/or a backpressure controlvalve 513 that are coupled to an exhaust line 515 configured to receiveevaporated refrigerant 517 from the cryotherapeutic device 520. Acontroller 518 can be operably coupled to the supply control valve 508and/or the backpressure control valve 513 to regulate refrigerant flowthrough the cryotherapeutic device 520. In the illustrated embodiment,the cryotherapeutic device 520 includes a shaft 522, a handle 525 at aproximal region of a proximal portion 524 of the shaft 522, and a distalportion 526 having a cooling assembly 530 at a distal end region of adistal portion 526 of the shaft 522.

As further shown in FIG. 5A, the console 502 can also include a pressuretransducer or sensor 570 (e.g., a PX209-100G5V pressure transducer madeby Omega Engineering of Stamford, Conn.) coupled to a pressure line 571to monitor pressure within a portion of the cooling assembly 530 (e.g.,an expansion chamber) during cryotherapy. In various embodiments, thepressure sensor 570 can be coupled to the controller 518 to serve as afeedback mechanism that controls the supply control valve 508 and/or thebackpressure control valve 513, and thereby regulates refrigerant flowto and/or from the cooling assembly 530 in response to a pressure sensedat the cooling assembly 530. For example, the pressure sensor 570 can beconfigured to indicate a pressure above a predetermined threshold (e.g.,within a range of a burst pressure of the expansion chamber). Inresponse, the controller 518 can decrease or terminate refrigerant flowby at least partially closing the supply control valve 508 and/orincreasing refrigerant flow from the cooling assembly 530 by decreasingthe backpressure in the exhaust line 515 (e.g., using the vacuum pump511). In other embodiments, the pressure sensor 570 can be coupleddirectly to the supply control valve 508 and/or the backpressure controlvalve 513 to automatically regulate the valves 508 and 513 on and/or offin response to a sensed pressure. In several embodiments, thecryotherapeutic system 500 can be configured to verify that the pressuresensor 570 is calibrated properly before cryotherapy. For example, thesystem 500 can automatically check the functionality of the pressuresensor 570 as the system 500 powers on by comparing a pressure readingfrom the pressure sensor 570 with the ambient pressure.

Referring now to FIG. 5B, the distal region of the cryotherapeuticdevice 520 can include features generally similar to the features of thecryotherapeutic device 120 described above with reference to FIGS.2A-2E. For example, the cryotherapeutic device 520 includes the supplylumen 132 coupled to the supply line 510 (FIG. 5A), the exhaust lumen134 coupled to the exhaust line 515 (FIG. 5A), and the applicator 140including the balloon 142 or other type of expandable member thatdefines the expansion chamber.

As shown in FIG. 5B, the cryotherapeutic device 520 can further includea pressure monitoring lumen 572 coupled to the pressure sensor 570 (FIG.5A) via the pressure line 571 (FIG. 5A). The pressure monitoring lumen572 can extend through the shaft 522 and have a distal opening 574 influid communication with the expansion chamber (e.g., defined by theballoon 142). The dimensions (e.g., cross-sectional area, innerdiameter, and/or outer diameter) of the pressure monitoring lumen 572can be large enough to sense a pressure reading within the expansionchamber with substantial accuracy, but small enough to reduce or preventinterference with the outflow of refrigerant through the exhaust lumen134. For example, the supply lumen 132 and the pressure monitoring lumen572 together can have a first cross-sectional dimension (e.g., a firstcross-sectional area) and the exhaust lumen 134 can have a secondcross-sectional dimension (e.g., a second cross-sectional area) suchthat the ratio of the second cross-sectional dimension to the firstcross-sectional dimension is between 4:1 and 10:1. In certainembodiments, the pressure monitoring lumen 572 can have an innerdiameter of no more than 0.03 inch (0.762 mm; e.g., 0.015 inch (0.381mm), 0.010 inch (0.762 mm), etc.) and an outer diameter of no more than0.060 inch (1.52 mm; e.g., 0.02 inch (0.508 mm), 0.015 inch (0.381 mm),etc.), and the exhaust lumen 134 can be sized accordingly. In theembodiment illustrated in FIG. 5B, the pressure monitoring lumen 572terminates in the shaft 522 before the outer diameter necks down at thesecond zone 127 b of the distal portion 520. This configuration may beused in embodiments where the inner diameter of the shaft 522 necks down(e.g., as shown in FIGS. 4A and 4B) so as not to restrict the venting ofthe expanded refrigerant 517 at the smaller second zone 127 b. In otherembodiments, the opening 574 of the pressure monitoring lumen 572 can beat or in the balloon 542.

The pressure monitoring lumen 572 can also have a length sufficient tointravascularly locate the opening 574 along with the cooling assembly530 at the target site T (e.g., a renal artery or renal ostium via afemoral artery or a radial artery). For example, the pressure monitoringlumen 572 can have a length equivalent to the full length of the shaft522 (e.g., at least 48 inches (122 cm)). In other embodiments, thepressure monitoring lumen 572 can have other suitable different lengthsand/or dimensions. For example, the pressure monitoring lumen 572 canhave a first length and the pressure line 571 attached thereto can havea second length (e.g., 48 inches (122 cm), 30 inches (76 cm), 12 inches(30 cm), etc.) to extend the pressure monitoring lumen 572 to thepressure sensor 570, thereby allowing the console 502 to be positionedin a desired location (e.g., on a table) during cryotherapeutictreatments.

During cryotherapeutic treatments, the pressure monitoring lumen 572 andthe pressure sensor 570 (FIG. 5A) may be configured to provide a signalindicating a change in pressure within the expansion chamber. Forexample, the pressure sensor 570 can be configured to indicate athreshold pressure below the rupture pressure of the balloon 142 toreduce the likelihood that the balloon 142 bursts during cryotherapy.The balloon 142 may have a burst pressure dependent at least in part onthe material from which the balloon 142 is made. Compliant materials(e.g., polyurethane), for example, typically have lower burst pressures(e.g., 80 psi, 100 psi, 200 psi, etc) than non-compliant materials(e.g., nylon) that can have burst pressures of 300 psi or higher. Thepressure sensor 570 can be configured to monitor a threshold pressure,which may be equal to a pressure value below the burst pressure thatprovides an adequate response time to react to the change in pressurebefore the balloon 142 ruptures. In other embodiments, the pressuresensor 570 can be configured to indicate when the balloon 142 operatesoutside its desired operating pressure (e.g., 20-60 psi).

The time delay between the pressure at the opening 574 of the pressuremonitoring lumen 572 at the expansion chamber and the pressure readingat the pressure sensor 570 may depend on the volume of the pressuremonitoring lumen 572. As such, the pressure monitoring lumen 572 canhave a volume that has a response time sufficient to adequately respondto the change in pressure in the expansion chamber (e.g., before ruptureof the balloon 142). In certain embodiments, for example, the pressuresensor 570 has a response time of less than 1.5 seconds, such as aresponse time of less than 1 second, 0.2 second, 0.1 second, or 15milliseconds. To enhance the accuracy of the pressure reading anddecrease the response time of the pressure sensor 570, the length of thepressure monitoring lumen 572 can be shortened and significant increasesin volume in the pressure monitoring lumen 572 before connecting to thepressure sensor 570 can be reduced. For example, the pressure monitoringlumen 572 can be coupled to the pressure line 571 at the proximalportion 524 (FIG. 5A) of the shaft 522 (e.g., at the handle 525), andthe pressure line 571 can have a cross-sectional area similar to that ofthe pressure monitoring lumen 572. In other embodiments, the pressuremonitoring lumen 572 can be coupled to the pressure sensor 570 at thehandle 525 (e.g., omitting the pressure line 571) to shorten the totallength of the pressure tube to the pressure sensor 570, and electricalwires can be coupled to the pressure sensor 570 to carry a signal to theconsole 502.

Referring to FIGS. 5A and 5B together, in certain embodiments, thepressure line 571 and/or the pressure monitoring lumen 572 can becoupled to the pressure sensor 570 using a fitting or adaptor 576 (e.g.,a quick connect adapter). In the embodiment illustrated in FIG. 5A, forexample, the adaptor 576 includes an internal reservoir or channel 578that fluidly connects the pressure line 571 with the pressure sensor570. The channel 578 can have a substantially small volume so as not todisrupt the pressure differential from the pressure line 571 to thepressure sensor 570 and enhance the accuracy of the pressuremeasurement. For example, in one embodiment, the channel 578 has aninternal volume of no more than 0.1 cc. In other embodiments, thechannel 578 can have a larger internal volume. In further embodiments,the adaptor 576 can couple the pressure monitoring lumen 572 to thepressure line 571 at the handle 525 or other position proximate theproximal portion 524 of the shaft 522. The adaptor 576, therefore,allows the pressure monitoring lumen 572 and/or the pressure line 571 tobe detached from the pressure transducer 570 after a cryotherapeutictreatment such that the pressure monitoring lumen 572 can be discardedand the pressure transducer 570 can be stored (e.g., along with thehandle 525 and/or the console 502) for subsequent cryotherapy treatmentswithout disrupting the accuracy of the pressure reading at the pressuresensor 570.

Referring back to FIG. 5B, in various other embodiments, thecryotherapeutic device 520 can further include an additional gas supplylumen 579 coupled to the supply container 504 (FIG. 5A) or other gassupply reservoir to deliver additional gas to the expansion chamber andthereby modulate the temperature of the applicator 140. For example, thegas supply lumen 579 can deliver the refrigerant 506 (e.g., nitrousoxide) and/or other pressurized or non-pressurized gas (e.g., air) intothe balloon 142 before or during delivery of the refrigerant 506 via theorifice 144 to increase the pressure within the balloon 142 (e.g., fromapproximately 5 psi to approximately 60 psi). The additional gas in theballoon 142 decreases the pressure drop of the refrigerant 506 in theexpansion chamber, and thereby increases the temperature within theballoon 142. As such, the gas supply lumen 579 can be used to initiate,restrict, and/or suspend the inflow of additional gas to the expansionchamber (e.g., using a valve) and regulate the temperature of theballoon 142 without requiring complex components in the console 502(e.g., a pressure regulator, a sub-cooler, etc.) to change the pressuredrop within the balloon 142. Additionally, when the gas supply lumen 579is coupled to a separate gas reservoir (e.g., an air supply), the gassupply lumen 579 can be used to deliver a gas into the balloon 142before delivering the refrigerant 506 into the balloon 142 to monitorthe position of the applicator 140 at the target site T.

In further embodiments, a pressure regulator (not shown; e.g., apressure relief valve) can be added to the exhaust lumen 134 to trap theevaporated refrigerant 517 from exiting the balloon 142 and/or in theexhaust lumen 134 until the pressure within the balloon 142 is at apredetermined value (e.g., as sensed using the pressure monitoring lumen572). In still further embodiments, the cryotherapeutic device 520 caninclude both a pressure regulator for the exhaust lumen 134 and the gassupply lumen 579 such that the pressure within the balloon 142 can bemodulated during cryotherapeutic treatment.

Pre-Cooling in Cryotherapeutic Systems

In cryogenic renal nerve modulation, the volume of refrigerant availablefor cooling can be limited. Accordingly, it can be useful to increasethe cooling capacity of a refrigerant. Pre-cooling the refrigerantbefore expanding the refrigerant in a cooling assembly is one example ofa process that can increase the cooling capacity of a refrigerant. Evenwhen cooling occurs primarily through phase change, using colderrefrigerant before the phase change can increase the amount of cooling.Moreover, if a supply tube is in thermal communication with an exhausttube, decreasing the temperature of refrigerant in the supply tube cancool refrigerant exhaust in the exhaust tube, which can reduce backpressure in an associated cooling assembly and thereby further increasecooling at the associated cooling assembly. Pre-cooling can reduce thevolume of refrigerant needed for cryogenic renal nerve modulation, whichcan allow smaller and more flexible shafts to be used within thevasculature. Pre-cooling also can mitigate reductions in coolingcapacity associated with other components of a cryotherapeutic system,such as thermally-insulative members within an applicator and in-linesolenoid valves that release heat during operation.

Pressurized refrigerant used in cryogenic renal nerve modulationtypically is supplied outside the vasculature at room temperature (e.g.,from a room-temperature dewar). As the pressurized refrigerant travelsalong a supply tube within the vasculature, it can increase intemperature via heat transfer with warm blood and tissue. For example,as pressurized refrigerant supplied at about room temperature (e.g.,about 23° C.) passes through the vasculature at body temperature (e.g.,about 37° C.), the temperature of the pressurized refrigerant canincrease to about 25° C. to 37° C. before reaching a cooling assembly.Cryotherapeutic devices configured in accordance with severalembodiments of the present technology can include a pre-cooling assemblyconfigured to cool pressurized refrigerant before the pressurizedrefrigerant expands in an associated cooling assembly. For example,pressurized refrigerant can be cooled to have a temperature just beforeexpansion in an associated cooling assembly that is less than bodytemperature (e.g., less than about 20° C. or less than about 10° C.).Such pre-cooling assemblies can be configured to be outside thevasculature and/or to utilize the same refrigerant supply as anassociated cooling assembly. In several embodiments configured inaccordance with the present technology, pre-cooling can be useful tomaintain refrigerant in liquid form until it reaches a cooling assemblywhere cryogenic cooling is desired. For example, evaporation associatedwith warming of refrigerant passing through portions of acryotherapeutic device proximal to a cooling assembly can be reduced. Inthis section, the terms “proximal” and “distal” can reference a positionrelative to a pressurized refrigerant source. For example, proximal canrefer to a position closer to a pressurized refrigerant source, anddistal can refer to a position farther from a pressurized refrigerantsource.

FIGS. 6A-6B illustrate a portion of a cryotherapeutic device 600including a pre-cooling assembly 602, an elongated shaft 604 defining anexhaust passage, and a hub 606 between the pre-cooling assembly and theshaft. The pre-cooling assembly 602 includes a flexible tubular member608 extending between the hub 606 and an adapter 610 configured toconnect to a pressurized-refrigerant source (not shown). The hub 606 caninclude a primary connector 612 attached to the shaft 604, an exhaustportal 614 venting to the atmosphere, a first branch 616 attached to thetubular member 608, and a second branch 618 attached to a control-wireconduit 620. In several embodiments, the hub 606 can include one or moreadditional branches, such as a branch including a tube fluidly connectedto a proximal syringe adapter (e.g., a proximal syringe adapterincluding a diaphragm configured to be punctured with a needle of asyringe). Such a structure can be useful, for example, to introducecontrast agent in the vicinity of a cooling assembly within thevasculature and/or to introduce filler material into a filler lumen of acooling assembly within the vasculature. Filler materials are discussedin greater detail below.

With reference again to FIGS. 6A-6B, two control wires 621 (FIG. 6B) canextend from the control-wire conduit 620, through the hub 606, and intothe shaft 604. The hub 606 can define a generally straightprimary-exhaust flow path from the shaft 604 to the atmosphere throughthe exhaust portal 614. The tubular member 608 includes a tubularproximal portion 622 at the adapter 610 and a tubular distal portion 624at the first branch 616. As most clearly shown in FIG. 6B, the tubularproximal portion 622 can include a first plug 626 and a second plug 628,and the adapter 610 can include an opening 630 proximate the second plug628. The adapter 610 can include a variety of suitable structures forconnection to a pressurized-refrigerant source, such as a threadedfitting, a compression fitting, or a barbed fitting.

In the embodiment shown in FIG. 6B, the device 600 includes aprimary-supply tube 632 defining a primary-supply lumen, and thepre-cooling assembly 602 includes a pre-cooling supply tube 634 defininga pre-cooling supply lumen. The primary-supply tube 632 and thepre-cooling supply tube 634 can include a primary-supply proximalopening 636 and a pre-cooling supply proximal opening 638, respectively,at the second plug 628. The primary-supply proximal opening 636 and thepre-cooling supply proximal opening 638 fluidly connect theprimary-supply tube 632 and the pre-cooling supply tube 634,respectively, to a passage defined by the opening 630. From the secondplug 628, the primary-supply tube 632 and the pre-cooling supply tube634 extend through the tubular proximal portion 622 and through thefirst plug 626. The tubular distal portion 624 defines a pre-coolingexpansion chamber extending from the first plug 626 to the primaryexhaust flow path. The pre-cooling supply tube 634 extends slightly pastthe first plug 626 and terminates at a pre-cooling distal opening 640within the pre-cooling expansion chamber. The pre-cooling expansionchamber is accordingly in fluid connection with a flow of refrigerantthrough the pre-cooling supply tube 634 such that a pre-cooling exhaustflow path extends from the pre-cooling distal opening 640 to the primaryexhaust flow path. The primary-supply tube 632 extends through thepre-cooling expansion chamber, through the hub 606 and into the shaft604. The portion of the primary-supply tube 632 extending fromprimary-supply proximal opening 636 to the shaft is a first portion ofthe primary-supply tube 632. A second portion (not shown) of theprimary-supply tube 632 is proximate a cooling assembly (not shown)configured to be within the vasculature.

Expanding pressurized refrigerant into the pre-cooling expansion chamberfrom the pre-cooling supply tube 634 can cool the pre-cooling expansionchamber and thereby cool the primary-supply tube 632 and liquidrefrigerant within the primary-supply tube. If pre-cooling is performeddistant from an entry point into the vasculature (e.g., if pressurizedrefrigerant is cooled in a console before being transported to an entrypoint into the vasculature), heat from the atmosphere can causeundesirable warming of the pre-cooled pressurized refrigerant.Positioning the pre-cooling expansion chamber proximate the hub canreduce such undesirable warming. A pre-cooling assembly configured inaccordance with several embodiments of the present technology can have alength sufficient to allow heat-transfer between expanded refrigerantwithin a pre-cooling expansion chamber and pressurized refrigerantwithin a portion of a primary-supply tube within the pre-coolingexpansion chamber. For example, a pre-cooling chamber configured inaccordance with several embodiments of the present technology can have alength greater than about 10 cm, such as greater than about 15 cm, orgreater than about 25 cm. A pre-cooling chamber configured in accordancewith several embodiments of the present technology has a length fromabout 20 cm to about 30 cm.

After cooling the primary-supply tube 632, refrigerant from thepre-cooling expansion chamber can join a flow of refrigerant from theexhaust passage and vent out the exhaust portal 614 to the atmosphere.FIG. 6B shows a first arrow 642 indicating a flow direction ofrefrigerant through the exhaust portal 614 and a second arrow 644indicating a flow direction of refrigerant through the pre-coolingexpansion chamber. The flow direction of refrigerant through the exhaustportal 614 is generally aligned with the exhaust passage. In contrast,the flow direction of refrigerant through the pre-cooling expansionchamber is not aligned with the exhaust passage or the flow direction ofrefrigerant through the exhaust portal 614.

FIG. 7 illustrates a portion of a cryotherapeutic device 700 similar tothe cryotherapeutic device 600 of FIGS. 6A-6B, except that the device700 has a pre-cooling expansion chamber fluidly separate from theexhaust passage. The cryotherapeutic device 700, for example, includes apre-cooling assembly 702 including a valve 704 and a third plug 706fluidly separating the pre-cooling expansion chamber from internalportions of the shaft 604 and the hub 606. The primary-supply tube 632extends through the third plug 706 and into the shaft 604.

An arrow 708 indicates a flow direction of refrigerant through thepre-cooling expansion chamber when the valve 704 is open. When the valve704 is closed, pressure within the pre-cooling expansion chamber canincrease until it equilibrates with the pre-cooling supply tube 634,thereby causing flow through the pre-cooling supply tube to stop. Inthis way, opening and closing the valve 704 can turn pre-cooling on oroff. Partially opening the valve 704 can regulate pressure within thepre-cooling expansion chamber and thereby regulate refrigerant flowthrough the pre-cooling supply tube 634 and an associated pre-coolingtemperature. For example, an actuator 710 can be operably connected tothe valve 704 and be configured to receive a signal from a processor712. The processor 712 can be configured to receive a signal from a userinterface 714 and/or a sensor 716 to direct the actuator 710 to open orclose the valve fully or incrementally. The sensor 716, for example, canbe a temperature sensor of an associated cooling assembly. In oneembodiment, the temperature sensor can send a signal to the processor712 causing the valve 704 to (a) open and pre-cooling to increase if adetected temperature of the cooling assembly or tissue proximate thecooling assembly is higher than a desired value, or to (b) close andpre-cooling to decrease if a detected temperature of the coolingassembly or tissue proximate the cooling assembly is lower than adesired value.

FIGS. 8A-8B illustrate a portion of a cryotherapeutic device 800 with apre-cooler 802 configured in accordance with another embodiment of thepresent technology. Accessing an internal portion of the tubular member608 to form the first plug 626 of the pre-cooling assembly 602 (FIGS.6A-6B) can be challenging. Instead of the first plug 626 and thepre-cooling supply tube 634 (FIG. 6B), the pre-cooler 802 can include aflow separator attached to a primary-supply tube. For example, thepre-cooler 802 can include a flow separator 804 attached to aprimary-supply tube 806 and a container 808 having a container proximalportion 810 and a container distal portion 812. In this embodiment, theflow separator 804 divides the container 802 into the container proximalportion 810 and the container distal portion 812. The container proximalportion 810 defines a proximal chamber or a combined supply lumenbetween the opening 630 and the flow separator 804 and the containerdistal portion 812 defines a pre-cooling expansion chamber. As mostclearly shown in FIG. 8B, the flow separator 804 defines a primarypassage 814 fluidly connected to the primary-supply tube 806 and apre-cooling passage 816 along a periphery of the flow separator 804.

Referring still to FIG. 8B, the pre-cooling passage 816 is sized tocause a pressure drop sufficient to expand refrigerant and cool thepre-cooling expansion chamber. The flow separator 804 includes a tubularsegment 818 and a flow-separator plug 820. The flow-separator plug 820is positioned between an outer surface of the primary-supply tube 806and an inner surface of the container 808. The tubular segment 818 canbe selected to have an outer cross-sectional dimension (e.g., diameter)slightly smaller than an inner cross-sectional dimension (e.g.,diameter) of the container 808. The flow-separator plug 820 can include,for example, an adhesive material configured to bond to the outersurface of the primary-supply tube 806 and the inner surface of thecontainer 808.

In one embodiment, the flow separator 804 floats in the container 808(i.e., it is not fixed within the container 808) such that thepre-cooling passage 816 is an annular space between the flow separator804 and an inner surface of the container 808. In other embodiments,flow separators can have different configurations. For example, a flowseparator can be fixed to the container and a pre-cooling passage canextend through the flow separator around only a portion of the peripheryof the flow separator, such as a curved portion. In still otherembodiments, the flow separator can be attached to the container aroundgenerally its entire circumference and the flow separator can include anopening spaced inwardly apart from the periphery of the flow separator.For example, a flow separator can include an internal opening configuredto expand refrigerant into the pre-cooling expansion chamber.

FIGS. 9A-9B illustrate a portion of a cryotherapeutic device 900 similarto the cryotherapeutic device 800 of FIGS. 8A-8B, except havingdifferent flow-separator and primary-supply tube configurations. Thecryotherapeutic device 900 includes a primary supply tube 902 and apre-cooler 904 including a flow separator 906 attached to theprimary-supply tube 902. The pre-cooler 904 can also include a container908 having a container proximal portion 910 and a container distalportion 912 on opposite sides of the flow separator 906. In thisembodiment, the flow separator 906 does not include a tubular segmentand can be constructed, for example, from a cylindrical block ofmaterial (e.g., rubber, polymer, metal, or another material) having ahole through which the primary-supply tube 902 can be threaded orotherwise attached. As most clearly shown in FIG. 9B, the flow separator906 can define a pre-cooling passage 914 along a periphery of the flowseparator 906. The primary-supply tube 902 can extend through the flowseparator 906 and can be attached to an inner surface of the containerproximal portion 910 proximate the opening 630. Attaching theprimary-supply tube 906 to an accessible portion of the containerproximal portion 910 can be useful to prevent undesirable longitudinalmovement of the flow separator 906 and the primary-supply tube 902 whenthe proximal chamber is at high pressure.

A pre-cooling assembly configured in accordance with several embodimentsof the present technology can be arranged in a compact configuration.For example, at least a portion of such a pre-cooling assembly can bewithin a handle of a cryotherapeutic device. FIG. 10 illustrates aportion of a cryotherapeutic device 1000 including a pre-coolingassembly 1002 and a hub 1004 within a handle 1006. The pre-coolingassembly 1002 includes a flexible tubular member 1008 extending from thehub 1004, through a bottom portion 1010 of the handle 1008, and to anadapter 1012 configured to connect to a pressurized-refrigerant source(not shown). The hub 1004 can include an elongated exhaust portal 1014extending through the bottom portion 1010, and a control-wire conduit1016 can extend from the hub 1004 through the bottom portion 1010. Inone embodiment, the tubular member 1008 is coiled around the exhaustportal 1014. The handle 1006 also can be insulated to prevent heat lossto the atmosphere and improve pre-cooling efficiency.

FIG. 11 illustrates a portion of a cryotherapeutic device 1100 having analternative configuration within and around a handle. Thecryotherapeutic device 1100 includes a pre-cooling assembly 1102 and ahub 1104 within a handle 1106. The pre-cooling assembly 1102 includes aflexible tubular member 1108 extending from the hub 1104 and through abottom portion 1110 of the handle 1106. The hub 1104 can include anelongated exhaust portal 1112 extending through the bottom portion 1110,and a control-wire conduit 1114 can extend from the hub 1104 through thebottom portion 1110. In one embodiment, the tubular member 1108 includesa helical portion 1116 spaced apart from the exhaust portal 1112. Thehandle 1106 also can be insulated to prevent heat loss to the atmosphereand improve pre-cooling efficiency.

Cryotherapeutic-Device Components

Having in mind the foregoing discussion of cryotherapeutic devicesconfigured in accordance with several embodiments of the presenttechnology, a variety of different cooling assemblies, occlusionmembers, and other cryotherapeutic-device components are described belowwith reference to FIGS. 12-55. It will be appreciated that thecryotherapeutic-device components described below and/or specificfeatures of the cryotherapeutic-device components described below can beused with the cryotherapeutic system 100 shown in FIG. 1, used in astandalone or self-contained handheld device, or used with anothersuitable system. For ease of reference, throughout this disclosureidentical reference numbers are used to identify similar or analogouscomponents or features, but the use of the same reference number doesnot imply that the parts should be construed to be identical. Indeed, inmany examples described herein, the identically-numbered parts aredistinct in structure and/or function.

Several embodiments of cryotherapeutic-device components described belowcan be configured to facilitate one or more treatment objectives relatedto cryogenic renal-nerve modulation. For example, several embodiments ofapplicators described below are configured to apply cryogenic cooling ina desirable localized or overall treatment pattern. A desirablelocalized treatment pattern can include, for example,partially-circumferential cooling at one or more longitudinal segmentsof a renal artery or a renal ostium. A desirable overall treatmentpattern can include a combination of localized treatment patterns at atreatment site. For example, a desirable overall treatment pattern canbe a partially-circumferential or a fully-circumferential treatmentpattern in a plane perpendicular to a renal artery or a renal ostium. Tofacilitate a desirable localized or overall treatment pattern, anapplicator configured in accordance with several embodiments of thepresent technology can have more than one heat-transfer portion, such asa primary heat-transfer portion and a secondary heat-transfer portion.When a cooling assembly including such an applicator is operating in adeployed state, a primary heat-transfer portion of the applicator canhave a heat-transfer rate sufficient to cause therapeutically-effective,cryogenic renal-nerve modulation. A secondary heat-transfer portion ofthe applicator can have a lower heat-transfer rate during operation,such as a heat-transfer rate insufficient to causetherapeutically-effective, cryogenic renal-nerve modulation. Thepositioning of the primary and secondary heat-transfer portions cancorrespond to a desirable localized or overall treatment pattern.

Several embodiments of applicators described below include featuresconfigured to affect the positioning of primary and secondaryheat-transfer portions. Such features can include, for example, featuresrelated to (a) differential convective heat-transfer within anapplicator, (b) differential conductive heat-transfer through anapplicator, and/or (c) differential contact or spacing between anapplicator and a renal artery or a renal ostium at a treatment site.Features related to differential convective heat transfer can include,for example, refrigerant supply tubes and orifices configured toselectively direct expansion of refrigerant toward different portions ofan applicator. Features related to differential conductive heat transferthrough an applicator can include, for example, additional balloons(e.g., non-cooling balloons and balloons having low levels of cooling),differential composition (e.g., low thermal conductivity and highthermal conductivity materials), differential thicknesses (e.g.,balloon-wall thicknesses), and thermally-insulative structures (e.g.,elongated, thermally-insulative members within balloons or attached toballoon walls). Features related to differential contact or spacingbetween an applicator and a renal artery or a renal ostium can include,for example, additional balloons, and characteristics of complexballoons, such as shape (e.g., helical, curved,longitudinally-asymmetrical, and radially-asymmetrical), surfacedifferentiation (e.g., recesses, groves, protrusions, and projections),and differential expansion (e.g., partially-constrained expansion).

Several embodiments of applicators described below are also configuredto facilitate sizing, such as delivery at a reduced (e.g., low-profile)cross-sectional dimension and deployment at a cross-sectional dimensionsuitable for providing therapeutically-effective treatment to renalarteries and/or renal ostiums having different sizes. For example,several embodiments of applicators described below include a balloonthat is at least partially collapsed when an associated cooling assemblyis in a delivery state and at least partially expanded when anassociated cooling assembly is in a deployed state. Features related tosizing can include, for example, balloon composition (e.g., compliantand non-compliant materials), additional balloons, and characteristicsof complex balloons, such as shape (e.g., compliant and non-compliantshapes). Non-compliant materials (e.g., polyethylene terephthalate) canhave compliance (e.g., elasticity), for example, from about 0% to about30%. Compliant materials (e.g., polyurethane and other thermoplasticelastomers) can have compliance, for example, from about 30% to about500%. Non-compliant materials typically have greater strength (e.g.,higher pressure ratings) than compliant materials. Several embodimentsof applicators described below can be configured to facilitate adesirable level of occlusion of a renal artery and/or a renal ostium.For example, several embodiments of applicators described below areconfigured to be partially occlusive, such as to applytherapeutically-effective cooling for renal nerve modulation at atreatment site without preventing blood flow through the treatment site.Features related to partial occlusion include, for example,characteristics of complex balloons, such as shape (e.g., helical,curved, longitudinally-asymmetrical, and radially-asymmetrical) anddifferential expansion (e.g., partially-constrained expansion). Fullocclusion, such as complete or near-complete blockage of blood-flowthrough a renal artery or a renal ostium can be desirable with regard tocertain treatments. Features related to full occlusion can include, forexample, any suitable feature related to sizing. As described below,cryotherapeutic devices configured in accordance with severalembodiments of the present technology can include an occlusion member,such as an expandable member of a cooling assembly (e.g., a balloondefining an expansion chamber) or a separate occlusion member (e.g.,proximal to a cooling assembly). An occlusion member can be combinedwith any suitable applicator described herein to provide occlusion inconjunction with features associated with the applicator.

Cooling assemblies configured in accordance with the present technologycan include structures that take advantage of frozen and/or liquid bloodproximate an applicator to facilitate one or more treatment objectivesrelated to cryogenic renal-nerve modulation. Frozen and/or liquid bloodproximate an applicator can affect factors such as heat transfer,sizing, and occlusion. For example, several embodiments can beconfigured to freeze blood around an applicator to cause full or partialocclusion. In some cases, therapeutically-effective cooling can occurthrough a layer of frozen blood (e.g. a layer of frozen blood having athickness less than about 0.8 mm, 1 mm, or 1.2 mm). A balloon can beconfigured such that frozen blood having a thickness through whichtherapeutically-effective cooling can occur is formed between a primaryheat-transfer portion of the balloon and a renal artery or a renalostium. This layer, for example, can facilitate sizing or a desiredlevel of occlusion. Moreover, a balloon can be configured such thatfrozen blood having a thickness through which therapeutically-effectivecooling cannot occur (e.g., a thickness greater than about 0.8 mm, 1 mm,or 1.2 mm) is formed between a secondary heat-transfer portion and arenal artery or a renal ostium. Such balloons can include, for example,recessed and non-recessed portions and other suitable structures asdescribed in greater detail below.

Convective Heat Transfer

FIGS. 12-16B illustrate several embodiments of cryotherapeutic devicesthat can use differential convective heat-transfer to affect atreatment. Features related to convective heat transfer within anapplicator can facilitate one or more treatment objectives of cryogenicrenal-nerve modulation, such as a desirable localized or overalltreatment pattern. Such features can include, for example, refrigerantsupply tubes and orifices configured to selectively direct expansion ofrefrigerant toward different portions of an applicator.

FIG. 12 illustrates a portion of a cryotherapeutic device 1200 includinga cooling assembly 1202 at a distal portion 1204 of an elongated shaft1206 defining an exhaust passage. As described above, the distal portion1204 can have a step 1208 and the cooling assembly 1202 can include anapplicator 1210 having a plurality of heat transfer portions(individually identified as 1211 a-d). The applicator 1210 also can havea balloon 1212 with a distal neck 1214, and the balloon 1212 can definean expansion chamber configured to generate and deliver cryogeniccooling. The device 1200 can further include an elongated guide member1216 a, a first supply tube 1218 defining a first supply lumen, and asecond supply tube 1220 defining a second supply lumen. The guide member1216 a can define a guide-wire lumen shaped to receive a guide wire 1216b, as described in greater detail above. Guide members described withrespect to other cryotherapeutic-device components described herein canbe similarly configured, although for clarity of illustration,associated guide wires typically are not shown. In the illustratedembodiment, the guide member 1216 a has a straight end and extends tothe distal neck 1214. Alternatively, the guide member 1216 a can includea rounded end and/or an end that extends beyond the distal neck 1214.Similarly, in other cryotherapeutic-device components described herein,illustrated ends of guide members and/or supply tubes that exit distalportions of balloons can have various suitable shapes (e.g., atraumaticshapes) and can extend varying distances relative to distal necks ofballoons.

The first supply tube 1218 can include a first angled distal portion1222, and the cooling assembly 1202 can include a first orifice 1224 atthe end of the first angled distal portion 1222. Similarly, the secondsupply tube 1220 can include a second angled distal portion 1226, andthe cooling assembly can include a second orifice 1228 at the end of thesecond angled distal portion. The first and second angled distalportions 1222, 1226 of the illustrated embodiment are longitudinally andradially spaced apart along and about the length of the cooling assembly1202. In several other embodiments, the first and second angled distalportions 1222, 1226 have the same longitudinal and/or radial position,or another configuration. When the cooling assembly 1202 is in adeployed state, refrigerant can flow through the first and second supplytubes 1218, 1220, flow through the first and second angled distalportions 1222, 1226, respectively, and flow out the first and secondorifices 1224, 1228, respectively. The first and second angled distalportions 1222, 1226 can direct expanded refrigerant toward theheat-transfer portions 1211 a and 1211 d, respectively. As a result,when refrigerant flows out of the first and second orifices 1224, 1228,the heat-transfer portions 1211 a and 1211 d can have higher overall andparticularly convective heat-transfer rates relative to otherheat-transfer portions of the applicator 1210. This variation inheat-transfer rate can correspond to a desired cooling pattern, such asa partially-circumferential cooling pattern at some or all longitudinalsegments of the applicator 1210. The difference in heat-transfer ratecan vary depending on a distance from the heat-transfer portions 1211 aand 1211 d. A functionally significant difference in heat-transfer ratecan separate the heat-transfer portion 1211 a from the heat-transferportion 1211 c, which is generally circumferentially opposite to theheat-transfer portion 1211 a. Similarly, a functionally significantdifference in heat-transfer rate can separate the heat-transfer portion1211 d from the heat-transfer portion 1211 b, which is generallycircumferentially opposite to the heat-transfer portion 1211 d. Inseveral embodiments, the heat-transfer portions 1211 a and 1211 d haveheat-transfer rates sufficient to cause therapeutically-effective renalnerve modulation, while the heat-transfer portions 1211 b and 1211 chave heat-transfer rates insufficient to cause therapeutically-effectiverenal nerve modulation.

The first and second supply tubes 1218, 1220 can be configured, forexample, to direct expansion of refrigerant at angles about 45° offsetfrom the length of the applicator 1210 or the length of the coolingassembly 1202. In several other embodiments, one or more supply tubesare configured to direct refrigerant at an angle from about 15° to about90° relative to a length of an applicator or a cooling assembly, such asfrom about 30° to about 45°, or from about 30° to about 40°.Additionally, the first supply tube 1218 can be at a different anglethan the second supply tube 1220. The longitudinal distance between afirst orifice 1224 and a second orifice 1228 of a cooling assemblyconfigured in accordance with several embodiments of the presenttechnology can be, for example, from about 1 mm to about 20 mm, such asfrom about 2 mm to about 15 mm, or from about 3 mm to about 10 mm.

Cooling assemblies configured in accordance with several embodiments ofthe present technology can alternatively include a supply tube or lumenhaving a curved and/or helical portion. FIG. 13 illustrates a portion ofa cryotherapeutic device 1300 including a cooling assembly 1302 at adistal portion 1304 of an elongated shaft 1306 defining an exhaustpassage open at the end of the distal portion 1304. The distal portion1304 can have a step 1307 and the cooling assembly 1302 can include anapplicator 1308 having a first heat-transfer portion 1309 and a secondheat-transfer portion 1310. The first and second heat-transfer portions1309, 1310 are elongated and radially spaced apart around the length ofthe cooling assembly 1302. The applicator 1308 also can have a balloon1311 that can define an expansion chamber configured to generate anddeliver cryogenic cooling. The device 1300 can further include anelongated guide member 1312 and a supply tube 1313 extending along thelength of the shaft 1306. Within the balloon 1311, the supply tube 1313can include a helical portion 1314 that exits the distal portion 1304and wraps around the distal portion 1304 (e.g., the distal portion 1304can define a central axis of the helical portion 1314). The coolingassembly 1302 can include a plurality of orifices (individuallyidentified as 1316 a-e) laterally spaced apart along the helical portion1314. In the illustrated embodiment, if the helical portion 1314 werestraightened, the orifices 1316 a-e would be generally radially aligned.In this embodiment, the shape of the helical portion 1314 causes theorifices 1316 a-e to point in different radial directions. In otherembodiments, the helical portion 1314 can have a different number and/ororientation of orifices 1316 a-e.

The helical portion 1314 locates the orifices 1316 a-e closer to theballoon 1311 than they would be if the supply tube 1312 were straight.This can cause refrigerant exiting the orifices 1316 a-e to contact theballoon 1311 at higher velocities and increase the amount of convectivecooling at corresponding heat-transfer portions of the balloon 1311.This can also provide more control of the size and spacing of whererefrigerant first contacts the balloon 1311. Cooling assembliesconfigured in accordance with several embodiments of the presenttechnology can include orifices spaced apart greater than about 0.01 mm(e.g., greater than about 0.1 mm, greater than about 0.5 mm, or greaterthan about 1 mm) from central longitudinal axes of cooling assemblieswhen the cooling assemblies are in a deployed state. For example,orifices in several embodiments can be between about 0.01 mm and about 4mm or between about 0.1 mm and about 2 mm from central longitudinal axesof cooling assemblies when the cooling assemblies are in a deployedstate. Similarly, cooling assemblies configured in accordance withseveral embodiments of the present technology can include orificesspaced apart by less than about 4 mm (e.g., less than about 2 mm, lessthan about 1 mm, or less than about 0.5 mm) from balloons when thecooling assemblies are in a deployed state. For example, orifices inseveral embodiments can be between about 0.1 mm and about 4 mm orbetween about 0.5 mm and about 2 mm apart from balloons when the coolingassemblies are in a deployed state. Furthermore, cooling assembliesconfigured in accordance with several embodiments of the presenttechnology can include an orifice positioned such that a distance from acentral longitudinal axis of a cooling assembly to the orifice is notless than about 20% (e.g., not less than about 25%, 40%, or 60%) of adistance from the central longitudinal axis to an inner surface of aballoon in a plane at the orifice and perpendicular to the centrallongitudinal axis.

In the illustrated embodiment, the orifices 1316 a, 1316 c, 1316 e pointgenerally toward an upper half of the balloon 1311, while the orifices1316 b, 1316 d point generally toward a lower half of the balloon 1311.When the cooling assembly 1302 is in a deployed state, refrigerant flowthrough orifices 1316 a, 1316 c, 1316 e produces the first heat-transferportion 1309, while refrigerant flow through orifices 1316 b, 1316 dproduces the second heat-transfer portion 1310. As a result of therefrigerant flow, the first and second heat-transfer portions 1309, 1310can have higher overall and particularly convective heat-transfer ratesrelative to other heat-transfer portions of the applicator 1308. Thisvariation in heat-transfer rate can correspond to a desired coolingpattern, such as a partially-circumferential cooling pattern at some orall longitudinal segments of the applicator 1308. In severalembodiments, the first and second heat-transfer portions 1309, 1310 haveheat-transfer rates sufficient to cause therapeutically-effective renalnerve modulation, while portions of the applicator 1308 between thefirst and second heat-transfer portions 1309, 1310 have heat-transferrates insufficient to cause therapeutically-effective renal nervemodulation.

FIG. 14 illustrates a portion of a cryotherapeutic device 1400 thatdiffers from the device 1300 of FIG. 13 primarily with respect to anexhaust configuration. The device 1400 includes a cooling assembly 1402at a distal portion 1404 of an elongated shaft 1406 defining an exhaustpassage. The distal portion 1404 can have a step 1407, a plurality ofexhaust openings 1408, and a rounded end 1409. The cooling assembly 1402can include an applicator 1410 with a balloon 1411 having a distal neck1412 and the balloon 1411 can define an expansion chamber configured togenerate and deliver cryogenic cooling. The device 1400 can furtherinclude a supply tube 1413 extending along the length of the shaft 1406and into the balloon 1411. Within the balloon 1411, the supply tube 1413can include a helical portion 1414 that exits the distal portion 1404and wraps around the distal portion 1404 (e.g., the distal portion 1404can define, a central axis of the helical portion 1414). The helicalcoils of the helical portion 1414 can be located between the exhaustopenings 1408. The cooling assembly 1402 can include a plurality oforifices (individually identified as 1416 a-d) laterally spaced apartalong the helical portion 1414. In the illustrated embodiment, thedistal portion 1404 is sufficiently narrow to allow the helical portion1414 to wrap around the distal portion 1404 generally without extendingbeyond the diameter of the shaft 1406 proximal to the distal portion1404. Accordingly, the cooling assembly 1402 in a delivery state can beconfigured to fit within a delivery sheath sized according to the shaft1406. The plurality of exhaust openings 1408 can promote exhaust flowand mitigate any flow restriction associated with the sizing of thedistal portion 1404. Thus, as discussed above, the relatively highdensity of expanded refrigerant entering the exhaust passage can allowthe distal portion 1404 to be sized down without necessarily causing anunsuitable increase in back pressure.

Similar to the orifices 1316 a-e of the device 1300 of FIG. 13, theorifices 1416 a-d in the illustrated embodiment are laterally spacedapart along the helical portion 1414. However, unlike the orifices 1316a-d of the device 1300 of FIG. 13, the orifices 1416 a-d in theillustrated embodiment are configured to direct refrigerant flow indifferent radial directions around the length of the cooling assembly1402. Specifically, the orifices 1416 a-d are configured to directrefrigerant flow in directions radially spaced apart by increments ofabout 90°. The orifices 1416 a-d are sized to cause correspondingheat-transfer portions having circumferential arcs greater than about90°. As a result, the projected circumference of the heat-transferportions corresponding to the orifices 1416 a-d is generally fullycircumferential, while being partially circumferential in particularlongitudinal segments of the cooling assembly 1402.

As discussed above with reference to FIG. 13, locating primaryrefrigerant expansion areas closer to a balloon can facilitateconvective heat transfer. FIGS. 15A-15B illustrate a portion of acryotherapeutic device 1500 that also can be configured to locateprimary refrigerant expansion areas closer to a balloon. The device 1500includes a cooling assembly 1502 at a distal portion 1504 of anelongated shaft 1506 defining an exhaust passage. The distal portion1504 can have a step 1507, and the cooling assembly 1502 can include anapplicator 1508 with an outer balloon 1510 that can define an expansionchamber configured to generate and deliver cryogenic cooling. The device1500 can further include a supply tube 1512 and an inner balloon 1514.The supply tube 1512 has a rounded end 1516 and can extend along thelength of the shaft 1506 and through a distal portion of the outerballoon 1510. The inner balloon 1514 extends around a portion of thesupply tube 1512 within the outer balloon 1510. In several otherembodiments configured in accordance with the present technology, asupply tube 1512 terminates within an inner distributor, such as theinner balloon 1514, and/or the device can include a guide member thatcan extend through the inner balloon 1514 and through the distal portionof the outer balloon 1510. With reference again to the embodiment of thedevice 1500 shown in FIGS. 15A-15B, the portion of the supply tube 1512within the inner balloon 1514 can include supply-tube orifices 1518. Thecooling assembly 1502 can include inner-balloon orifices 1520distributed in a helical arrangement or other suitable arrangement onthe inner balloon 1514. The inner-balloon orifices 1520 can be, forexample, laser-cut holes in the inner balloon 1514. When the coolingassembly 1502 is in a delivery state, the outer balloon 1510 and theinner balloon 1514 can be at least partially collapsed to fit within adelivery sheath.

When the cooling assembly 1502 is in a deployed state, refrigerant canflow from the supply tube 1512, through the supply-tube orifices 1518,and into the inner balloon 1514. The supply-tube orifices 1518 can belarge enough to allow refrigerant to enter the inner balloon 1514without liquid-to-gas phase change of a significant portion of liquidrefrigerant (e.g., a majority of liquid refrigerant). For example, inthe deployed state, a refrigerant absolute vapor pressure within theinner balloon 1514 outside the supply tube 1512 can be from about 40% toabout 100% of a refrigerant absolute vapor pressure within the portionof the supply tube within the inner balloon 1514, such as from about 20%to about 100%, or from about 33% to about 100%. A first free-passagearea equal to the total free-passage area of the inner-balloon orifices1520 can be less than a second free-passage area equal to the totalfree-passage area of the supply-tube orifices 1518. The size and/ornumber of inner-balloon orifices 1520 can be selected to control thefirst free-passage area. Similarly, the size and/or number ofsupply-tube orifices 1518 can be selected to control the secondfree-passage area. From the inner balloon 1514, refrigerant can expandthrough the inner-balloon orifices 1520 to cool one or morecorresponding heat-transfer portions of the applicator 1508. Inparticular, the inner-balloon orifices 1520 can be configured to cool agenerally helical heat-transfer portion.

FIGS. 16A-16B illustrate a cryotherapeutic device 1600 that differs fromthe cooling assembly 1500 of FIG. 15A with respect to an outer-balloonshape. The device 1600 includes a cooling assembly 1602 including anapplicator 1604 with an outer balloon 1606 having a raised helicalportion 1608 and a recessed portion 1610. The inner surface of theraised helical portion 1608 can be configured to receive expandedrefrigerant from the inner-balloon orifices 1520, and the shape of theinner surface of the raised helical portion 1608 can help to localizeincreased convective cooling at the raised helical portion 1608. Therecessed portion 1610 is generally configured not to contact a renalartery or a renal ostium. Localizing increased convective cooling to theraised helical portion 1606 can promote cooling efficiency as well ascooling-location selectivity. The raised helical portion 1608 cancorrespond to a heat-transfer portion having a higher heat-transfer ratethan other heat-transfer portions of the applicator 1604, such as aheat-transfer portion corresponding to the recessed portion 1610. Forexample, during operation, the raised helical portion 1608 cancorrespond to a heat-transfer portion having a heat-transfer ratesufficient to cause therapeutically-effective renal nerve modulation,while another heat-transfer portion of the applicator (e.g., aheat-transfer portion corresponding to the recessed portion 1610) has aheat-transfer rate insufficient to cause therapeutically-effective renalnerve modulation.

Conductive Heat Transfer

FIGS. 17A-22B illustrate several embodiments of cryotherapeutic devicesthat can use differential conductive heat-transfer to affect atreatment. Features related to conductive heat transfer through anapplicator can facilitate one or more treatment objectives of cryogenicrenal-nerve modulation, such as a desirable localized or overalltreatment pattern. In several embodiments, the devices controlconduction using thermally-insulative members. Features related todifferential conductive heat transfer through an applicator can include,for example, additional balloons (e.g., non-cooling balloons andballoons having low levels of cooling), differential composition (e.g.,low thermal conductivity and high thermal conductivity materials),differential thicknesses (e.g., balloon-wall thicknesses), andthermally-insulative structures (e.g., elongated, thermally-insulativemembers within balloons or attached to balloon walls).

FIGS. 17A-17B illustrate a portion of a cryotherapeutic device 1700including a cooling assembly 1702 at a distal portion 1704 of anelongated shaft 1706 defining an exhaust passage. The distal portion1704 can have a step 1707, and the cooling assembly 1702 can include anapplicator 1708 having a balloon 1710 configured to contact a renalartery or a renal ostium. The applicator 1708 can further include aplurality of elongated, thermally-insulative members 1711 with lengthsgenerally parallel to the length of the cooling assembly 1702 andradially spaced apart around the circumference of the cooling assembly1702. The balloon 1710 can define an expansion chamber configured togenerate and deliver cryogenic cooling. The device 1700 can furtherinclude a supply tube 1712 extending along the length of the shaft 1706and into the balloon 1710, and the cooling assembly 1702 can include anorifice 1714 at the end of the supply tube 1712. During operation whenthe cooling assembly 1702 is in a deployed state, thethermally-insulative members 1711 can reduce conductive cooling throughadjacent portions of the balloon 1710. For example, portions of theballoon 1710 between the thermally-insulative members 1711 can haveheat-transfer rates sufficient to cause therapeutically-effective renalnerve modulation, while portions of the balloon at thethermally-insulative members 1711 can have lower heat-transfer rates,such as heat-transfer rates insufficient to causetherapeutically-effective renal nerve modulation. Thethermally-insulative members 1711 can be elongated and generallycontinuous along the length of portions of the applicator 1708.Accordingly, heat-transfer portions corresponding to portions of theballoon 1710 between the thermally-insulative members 1711 can begenerally non-circumferential at longitudinal segments of the coolingassembly 1702.

The thermally-insulative members 1711 can include a primary materialhaving a thermal conductivity lower than or equal to a thermalconductivity of a primary material of the balloon 1710. In severalembodiments, the thermally-insulative members 1711 have differentcompositions than the balloon 1710 and are attached to an inner surfaceof the balloon 1710. Several other embodiments can includethermally-insulative members 1711 that are compositionally similar to(e.g., the same as) or different than the balloon 1710. Suitable primarymaterials for a thermally-insulative member configured in accordancewith several embodiments of the present technology includethermally-insulative polymer foams (e.g., polyurethane foams). Inseveral embodiments, a thermally-insulative member 1711 can beintegrally formed with a balloon 1710 or attached to a balloon 1710.

FIGS. 18A-18B illustrate a portion of a cryotherapeutic device 1800similar to the device 1700 of FIGS. 17A-17B except with regard to aconfiguration of thermally-insulative members. Thermally-insulativemembers configured in accordance with several embodiments of the presenttechnology can have different insulative properties in the deliverystate than in deployed state. For example, a thermally-insulative membercan be configured to be filled with a filler material in the deployedstate. The device 1800 includes a cooling assembly 1802 having anapplicator 1804 with a balloon 1806 that can define an expansion chamberconfigured to generate and deliver cryogenic cooling. The applicator1804 also includes a plurality of thermally-insulative members 1808. Thedevice 1800 can further include a filler tube 1810, and thethermally-insulative members 1808 can be configured to be filled in thedeployed state via the filler tube 1810. In the illustrate embodiment,the filler tube 1810 includes a main portion 1812 and four branches1814, in which the branches fluidly connect the main portion with one ofthe thermally-insulative members 1808. The thermally-insulative members1808 and the filler tube 1810 are fluidly separate from the expansionchamber within the balloon 1806.

The filler tube 1810 has a proximal portion (not shown) configured toreceive filler material from a filler-material source (not shown) fromoutside the vasculature. The filler tube 1810 and thethermally-insulative members 1808 can be configured to be fully, mostly,or partially collapsed in the delivery state. This can be useful toallow the introduction of fluidic filler material in the delivery statewithout the need to vent displaced gas. Several other embodiments caninclude a filler tube that is generally not collapsible and athermally-insulative member configured to receive displaced gas orliquid from such a filler tube. A proximal portion of a filler tubeconfigured in accordance with several embodiments of the presenttechnology can be fluidly connected to a filler port, such as a fillerport including syringe adapter, such as a syringe adapter including adiaphragm configured to be punctured with a needle of a syringecontaining filler material. Such a filler port can be configured, forexample, to reduce (e.g., prevent) passage of air before, during, and/orafter passage of filler material. However, in several embodiments, aircan be a suitable filler material. Other components of cryotherapeuticdevices configured in accordance with several embodiments of the presenttechnology including a filler tube (including such embodiments describedherein) can be similarly configured. Suitable filler materials for usewith cryotherapeutic devices configured in accordance with severalembodiments of the present technology include liquids (e.g., saline),gases (e.g., air), biologically inert materials, and radiopaquematerials (e.g., contrast agents).

Although four thermally-insulative members are shown in FIGS. 17A-18B,cooling assemblies configured in accordance with several embodiments ofthe present technology can include any suitable number ofthermally-insulative members, such as at least one or morethermally-insulative members. Additionally, thermally-insulative membersconfigured in accordance with several embodiments of the presenttechnology can be generally separate elements or portions of a singleelement and can have a variety of suitable shapes.

FIGS. 19A-19C illustrate a portion of a cryotherapeutic device 1900.Referring to FIG. 19A, the device 1900 can include a cooling assembly1902 at a distal portion 1904 of an elongated shaft 1906 defining anexhaust passage. The distal portion 1904 can have a step 1907, and thecooling assembly 1902 can include an applicator 1908 with a balloon 1910that can define an expansion chamber configured to generate and delivercryogenic cooling. The device 1900 can further include a supply tube1912 extending along the length of the shaft 1906 and into the balloon1910, and the cooling assembly 1902 can include an orifice 1914 at anend of the supply tube 1912. The device 1900 can further include ahelical thermally-insulative member 1916 that can be, for example, athicker portion of the balloon 1910 with the extra thickness at an innersurface of the balloon 1910 (i.e., an outer surface of the balloon 1910can be generally smooth or otherwise even at the helicalthermally-insulative member 1916 and around the helicalthermally-insulative member 1916). During operation when the coolingassembly 1902 is in a deployed state, the helical thermally-insulativemember 1916 can correspond to a heat-transfer portion of the applicator1908 having a lower heat-transfer rate than other portions of theapplicator 1908. For example, a heat-transfer rate of a portion of theapplicator 1908 apart from the helical thermally-insulative member 1916can be sufficient to cause therapeutically-effective renal nervemodulation during operation, while a heat-transfer rate of a portion ofthe applicator 1908 at the helical thermally-insulative member 1916 canbe insufficient to cause therapeutically-effective renal nervemodulation. FIGS. 19B and 19C are cross-sectional views of theapplicator 1908 at different longitudinal positions. As shown in FIGS.19B and 19C, the circumferential position of the helicalthermally-insulative member 1916 changes along the length of the coolingassembly 1902 such that the portion of the balloon 1910 apart from thehelical thermally-insulative member 1916 is generallynon-circumferential in longitudinal segments along the length of thecooling assembly 1902.

FIGS. 20A-20C illustrate a portion of a cryotherapeutic device 2000similar to the device 1900 of FIGS. 19A-19C except with regard to athermally-insulative member shape. Referring to FIG. 20A, the device2000 includes a cooling assembly 2002 having an applicator 2004 with aballoon 2006 that can define an expansion chamber configured to generateand deliver cryogenic cooling. The applicator 2004 also includes athermally-insulative member 2008 generally resembling an intertwineddouble helix (e.g., an intertwined right-handed helix and left-handedhelix). A heat-transfer portion of the applicator 2004 at thethermally-insulative member 2008 generally isolates heat-transferportions of the applicator 2004 apart from the thermally-insulativemember 2008. The thermally-insulative member 2008 can be configured tocollapse and/or expand with the balloon 2006 when the cooling assembly2002 moves between the delivery state and the deployed state. Forexample, if the balloon 2006 is generally flexible and non-compliant,the thermally-insulative member 2008 can be either generally flexibleand compliant or non-compliant. If the balloon 2006 is generallycompliant, the thermally-insulative member 2008 can be generallycompliant so as to compliantly expand and contract in conjunction withthe balloon 2006. The thermally insulative members 1716, 1808 shown inFIGS. 17A-18B, and the helical thermally-insulative member 1916 shown inFIGS. 19A-19B, can be similarly configured relative to the correspondingballoons 1710, 1806, 1910. In several embodiments of the presenttechnology, a thermally-insulative member has a modulus of elasticitybetween about 50% and about 150% of a modulus of elasticity of acorresponding balloon, such as between about 20% and about 140%, orbetween about 33% and about 130%.

Thermally-insulative members configured in accordance with additionalembodiments of the present technology can be fully or partially attachedto a corresponding balloon, or in other embodiments, thethermally-insulative members are not attached to the balloon. When athermally-insulative member is only partially attached or not attachedto a corresponding balloon, expansion and/or contraction of thecorresponding balloon can be relatively independent of thethermally-insulative member. FIGS. 21A-21C illustrate a portion of acryotherapeutic device 2100 including a cooling assembly 2102 at adistal portion 2104 of an elongated shaft 2106 defining an exhaustpassage. The distal portion 2104 can have a step 2107 and a rounded lip2108. The cooling assembly 2102 can include an applicator 2109 with aballoon 2110 having a distal neck 2111 and the balloon 2110 can definean expansion chamber configured to generate and deliver cryogeniccooling. The device 2100 can further include an elongated guide member2112 and a supply tube 2114 extending along a length of the shaft 2106and into the balloon 2110. The cooling assembly 2102 can include anorifice 2116 at the end of the supply tube. In the illustratedembodiment, the guide member 2112 extends through to the distal neck2111. The applicator 2109 further includes a first elongated,thermally-insulative member 2118 and a second elongated,thermally-insulative member 2120. The first and second elongated,thermally-insulative members 2118, 2120 are not attached to the balloon2110. Instead, the first and second elongated, thermally-insulativemembers 2118, 2120 are attached to an inner surface of the distalportion 2104.

When the cooling assembly 2102 is in a deployed state, the first andsecond thermally-insulative members 2118, 2120 can be movable relativeto the balloon 2110 in response to gravity. The first and secondthermally-insulative members 2118, 2120 can move over the rounded lip2108 as they settle within the balloon. As shown in FIG. 21A, the firstand second thermally-insulative members 2118, 2120 can settle along alower portion of the balloon 2110. As shown in FIG. 21B, the first andsecond thermally-insulative members 2118, 2120 have cross-sectionalareas resembling rounded triangles. In other embodiments, a similarthermally-insulative member can have a different cross-sectional area. Arounded triangular cross-sectional area can be particularly useful toincrease a contact area between a side of a generally unattachedthermally-insulative member and an inner surface of a balloon whilepreventing multiple generally unattached thermally-insulative membersfrom overlapping. With reference to FIG. 21C, the device 2100 is shownin the delivery state within a delivery sheath 2122. As shown in FIG.21C, the first and second thermally-insulative members 2118, 2120 cancollapse with the balloon 2110 in the delivery state.

FIGS. 22A-22B illustrate a portion of a cryotherapeutic device 2200similar to the device 2100 of FIGS. 21A-21C except with regard to aconfiguration of thermally-insulative members. The device 2200 includesa cooling assembly 2202 having an applicator 2204 with a balloon 2206that can define an expansion chamber configured to generate and delivercryogenic cooling. The applicator 2204 also includes a first elongated,thermally-insulative member 2208 and a second thermally-insulativemember 2210. The device 2200 can further include a filler tube 2212 andthe first and second thermally-insulative members 2208, 2210 can beconfigured to be filled in the deployed state via the filler tube 2212.The filler tube 2212 can include a hub 2214 where it branches into thefirst and second thermally-insulative members 2208, 2210. As discussedabove with reference to the thermally-insulative members 1808 of thedevice 1800 shown in FIGS. 18A-18B, the first and secondthermally-insulative members 2208, 2210 and the filler tube 2212 can befluidly separate from the balloon 2206. The filler tube 2212 can have aproximal portion (not shown) configured to receive filler material fromoutside the vasculature. The filler tube 2212 and the first and secondthermally-insulative members 2208, 2210 can be configured to be fully,mostly, or partially collapsed when the cooling assembly 2202 is in adelivery state.

A cooling assembly configured in accordance with several embodiments ofthe present technology can include one or more thermally-insulativemembers having a variety of suitable shapes to cause different patternsof heat-transfer portions around an applicator. A pattern can beselected, for example, so that a generally uninterrupted heat-transferportion at a thermally-insulative member can be large enough tosufficiently localize cooling therapeutically-effective for renal nervemodulation (e.g., such that cooling therapeutically-effective for renalnerve modulation generally does not bridge across a heat-transferportion at a thermally-insulative member). In addition or instead, apattern can be selected, for example, so that a heat-transfer portionspaced apart from a thermally-insulative member is large enough to allowtherapeutically-effective cooling for renal nerve modulation. Heattransfer is proportional to area, so if a heat-transfer portion spacedapart from a thermally-insulative member is too small, the total heattransfer through that part of the heat transfer portion can beinadequate to cause therapeutically-effective cooling for renal nervemodulation.

Complex Balloons

FIGS. 23A-37 illustrate several embodiments of cryotherapeutic devicesthat include complex balloons which can facilitate one or more treatmentobjectives related to cryogenic renal-nerve modulation, such as adesirable localized or overall treatment pattern, sizing, and partialocclusion. Complex balloons can have a variety of suitablecharacteristics, such as shape (e.g., helical, curved,longitudinally-asymmetrical, and radially-asymmetrical), surfacedifferentiation (e.g., recesses, groves, protrusions, and projections),and differential expansion (e.g., partially-constrained expansion).

FIGS. 23A-23B illustrate a portion of a cryotherapeutic device 2300including a cooling assembly 2302 at a distal portion 2304 of anelongated shaft 2306 defining an exhaust passage. The distal portion2304 can have a step 2307, a first exhaust port 2308, a second exhaustport 2309, and a rounded end 2310. The cooling assembly 2302 can includean applicator 2311 having a first balloon 2312 that defines a firstexpansion chamber and a second balloon 2313 that defines a secondexpansion chamber. The first balloon 2312 and the second balloon 2313are fluidly connected to the exhaust passage through the first exhaustport 2308 and the second exhaust port 2309, respectively. The device2300 can further include a supply tube 2314 extending along a length ofthe shaft 2306, and the cooling assembly 2302 can further include afirst orifice 2316 and a second orifice 2318. The first orifice 2316 isaligned with the first exhaust port 2308 such that refrigerant expandsthrough the first exhaust port 2308 and into the first balloon 2312, andthe second orifice 2318 is aligned with the second exhaust port 2309such that refrigerant expands through the second exhaust port 2309 andinto the second balloon 2313.

The first and second balloons 2312, 2313 are spaced apart along thelength of the cooling assembly 2302 and configured to expand laterallyacross different partially-circumferential arcs along the length of thecooling assembly 2302. When the cooling assembly 2302 is in a deployedstate, the first balloon 2312 can be configured to contact a firstpartially-circumferential portion of an inner surface of a renal arteryor a renal ostium, and the second balloon 2313 can be configured tocontact a second partially-circumferential portion of the inner surfaceof the renal artery or the renal ostium. The first and secondpartially-circumferential portions can have a fully-circumferentialcombined projection in a plane perpendicular to a length of the renalartery or the renal ostium. Accordingly, when a treatment calls forpartially-circumferential cooling at longitudinal segments and afully-circumferential overall cooling pattern, the cooling assembly 2302can be configured to facilitate such a treatment without repositioningthe cooling assembly 2302 during the treatment.

When the first and second balloons 2312, 2313 are both in the deployedstate, they can urge each other toward generally opposite sides of aninner surface of a renal artery or a renal ostium. For example, thedistal portion 2304 can transfer forces between the first and secondballoons 2312, 2313 while a portion of the shaft 2306 proximal to thedistal portion holds the distal portion generally parallel to a lengthof a renal artery or a renal ostium. During this and other operation,the cooling assembly 2302 can be configured to be non-occlusive (i.e.,to less than fully occlude a renal artery or a renal ostium). Forexample, the cooling assembly 2302 can be configured to allow apercentage of normal blood flow through a renal artery or a renal ostium(e.g., at least about 1%, at least about 10%, or at least about 25% ofnormal blood flow).

FIGS. 24A-24B illustrate a portion of a cryotherapeutic device 2400 thatdiffers from the device 2300 of FIGS. 23A-23B primarily with respect toan exhaust configuration. The device 2400 includes a cooling assembly2402 at a distal portion 2404 of an elongated shaft 2406 defining anexhaust passage. The distal portion 2404 can have a step 2407, a firstexhaust port 2408, a second exhaust port 2409, and a rounded end 2410.The cooling assembly 2402 can include an applicator 2411 having a firstballoon 2412 that defines a first expansion chamber and a second balloon2413 that defines a second expansion chamber. The first balloon 2412 andthe second balloon 2413 are fluidly connected to the exhaust passagethrough the first exhaust port 2408 and the second exhaust port 2409,respectively. The device 2400 can further include a supply tube 2414extending along a length of the shaft 2406 and having a first lateralbranch 2416 and a second lateral branch 2418. The cooling assembly 2402can further include a first orifice 2420 at the end of the first lateralbranch 2416 open to the first balloon 2412 and a second orifice 2422 atthe end of the second lateral branch 2418 open to the second balloon2413. Unlike the device 2300 shown in FIGS. 23A-23B, the device 2400includes refrigerant supply and refrigerant exhaust at circumferentiallyopposite sides of the distal portion 2404 for the first and secondballoons 2412, 2413. The first and second balloons 2412, 2413 extendaround fully-circumferential longitudinal segments of the distal portion2404, but are attached to the distal portion 2404 and shaped so as toexpand asymmetrically about the distal portion 2404.

Cooling assemblies configured in accordance with several embodiments ofthe present technology can include a different number ofpartially-circumferential balloons from the cooling assemblies 2302,2402 shown in FIGS. 23A-24B. For example, in several embodiments, thecooling assembly 2302 can include the first balloon 2312 or the secondballoon 2313 rather than both. Similarly, the cooling assembly 2402 caninclude the first balloon 2412 or the second balloon 2413 rather thanboth. The cooling assemblies 2302, 2402 shown in FIGS. 23A-24B also caninclude a greater number of balloons, such as three or four balloonslongitudinally and radially spaced apart. Furthermore, the sizes of theballoons can vary. For example, in several embodiments, the first andsecond balloons 2312, 2313 of the cooling assembly 2302 or the first andsecond balloons 2412, 2413 of the cooling assembly 2402 are configuredto provide a partially-circumferential overall cooling pattern.

Cooling assemblies configured in accordance with several embodiments ofthe present technology can include applicators with balloons having avariety of suitable surface characteristics, such as surfacecharacteristics configured to facilitate partially-circumferentialcooling at longitudinal segments alone or in combination with afully-circumferential overall cooling pattern. FIG. 25 illustrates aportion of a cryotherapeutic device 2500 including a cooling assembly2502 at a distal portion 2504 of an elongated shaft 2506 defining anexhaust passage. The distal portion 2504 can have a step 2507, and thecooling assembly 2502 can include an applicator 2508 with a balloon 2510that defines an expansion chamber and has a distal neck 2511, a helicalrecess 2512, and a non-recessed portion 2513. The device 2500 canfurther include an elongated guide member 2514 that extends through thedistal neck 2511, as well as a supply tube 2516 that extends along thelength of the shaft 2506 and into the balloon 2510. The cooling assembly2502 can further include an orifice 2518 at the distal end of the supplytube 2516. When the cooling assembly 2502 is in a delivery state, thehelical recess 2512 can correspond to a heat-transfer portion of theapplicator 2508 having a lower heat-transfer rate than portions of theapplicator 2508 spaced apart from the helical recess 2512.

The space between the helical recess 2512 and an inner surface of arenal artery or a renal ostium at a treatment site can thermallyinsulate portions of the renal artery or the renal ostium closest to thehelical recess 2512 from a cryogenic temperature within the balloon2510. For example, frozen or liquid blood within this space can providethermal insulation. The depth of the helical recess 2512 relative to thenon-recessed portion 2513 can be, for example, a depth corresponding toa thickness of material (e.g., liquid or frozen blood) sufficient tothermally insulate a portion of a renal artery or a renal ostium fromcryogenic cooling within the balloon 2510. For example, the depth can bebetween about 0.2 mm and about 2 mm, such as between about 0.3 mm andabout 1.5 mm. Recessed portions of balloons in several other embodimentsof cryotherapeutic-device components described herein can have similardepths relative to non-recessed portions of the balloons.

FIG. 26 illustrates a portion of another embodiment of a cryotherapeuticdevice 2600 including a cooling assembly 2602 at a distal portion 2604of an elongated shaft 2606 defining an exhaust passage. The distalportion 2604 can have a step 2607, and the cooling assembly 2602 caninclude an applicator 2608 with a balloon 2610 that defines an expansionchamber and has a distal neck 2611, a plurality of recesses 2612, and anon-recessed portion 2613. The recesses 2612 can be arranged in ahelical pattern around the circumference of the balloon 2610. Thecooling assembly 2602 can further include an elongated guide member 2614that extends through the distal neck 2611. The device 2600 can alsoinclude a supply tube 2616 that extends along the length of the shaft2606 and into the balloon 2610. The cooling assembly 2602 can furtherinclude an orifice 2618 at the distal end of the supply tube 2616. Whenthe cooling assembly 2602 is in a deployed state, the recesses 2612 andthe non-recessed portion 2613 can function similarly to the helicalrecess 2512 and the non-recessed portion 2513 of the device 2500 shownin FIG. 25.

FIGS. 27A-27C illustrate a portion of a cryotherapeutic device 2700similar to the device 2600 of FIG. 26, but the device 2700 is configuredto be less occlusive within a renal artery or a renal ostium than thedevice 2600 of FIG. 26. The device 2700 includes a cooling assembly 2702at a distal portion 2704 of an elongated shaft 2706 defining an exhaustpassage. The distal portion 2704 can have a step 2707, and the coolingassembly 2702 can include an applicator 2708 with a balloon 2710 thatdefines an expansion chamber and has proximal branches 2711, a tubularmain portion 2712, distal branches 2713, a plurality of recesses 2714,and a non-recessed portion 2716. The plurality of recesses 2714 can bearranged in a helical pattern around the circumference of the balloon2710. When the cooling assembly 2702 is in a deployed state, therecesses 2714 and the non-recessed portion 2716 can function similarlyto the recesses 2612 and the non-recessed portion 2613 of the device2600 shown in FIG. 26. The proximal branches 2711 can be configured tofluidly connect the tubular main portion 2712 to the exhaust passage.The device 2700 can further include an elongated guide member 2718 thatcan extend along the length of the shaft 2706 and attach to the distalbranches 2713, as well as a supply tube 2720 that extends along thelength of the shaft 2706, through one of the proximal branches 2711, andinto the tubular main portion 2712. The proximal branches 2711 and thedistal branches 2713 can be configured to space apart the tubular mainportion 2712 from the guide member 2718. The cooling assembly 2702 canfurther include an orifice 2722 at the distal end of the supply tube2720.

When the cooling assembly 2702 is in a deployed state, the coolingassembly 2702 can define a flow path (e.g., a blood flow path) betweenan outside surface of the guide member 2718 and the balloon 2710. Theflow path can extend, for example, around the proximal branches 2711,through the tubular main portion 2712 (e.g., between the guide member2718 and an inner surface of the tubular main portion 2712), and aroundthe distal branches 2713. As shown in FIG. 27B, the tubular main portion2712 can include a thermally-insulative inner portion 2724 around theflow path. The thermally-insulative inner portion 2724 can be configuredto at least partially insulate fluid in the flow path from cryogeniccooling within the tubular main portion 2712. In the illustratedembodiment, the thermally-insulative inner portion 2724 can be a portionof the balloon 2710 having a greater thickness than other portions ofthe balloon 2710. In several other embodiments, the thermally-insulativeinner portion 2724 has a different composition from other portions ofthe balloon 2710 and/or includes one or more separatethermally-insulative structures. Alternatively, the balloon 2710 caninclude a tubular main portion 2712 with an inner portion that is notmore thermally insulative than other portions of the balloon 2710.

FIG. 28 illustrates a portion of a cryotherapeutic device 2800 similarto the device 2600 of FIG. 26 except with regard to a configuration ofrecessed and non-recessed portions. The device 2800 includes a coolingassembly 2802 having an applicator 2804 with a balloon 2806 that candefine an expansion chamber. The balloon 2806 includes a plurality ofprotrusions 2808 and a non-protruding portion 2810. The protrusions 2808can be arranged in a helical pattern or other suitable pattern aroundthe circumference of the balloon 2806. When the cooling assembly 2802 isin a delivery state, the non-protruding portion 2810 can correspond to aheat-transfer portion of the applicator 2804 having a lowerheat-transfer rate than portions of the applicator at the protrusions2808. The space between the non-protruding portion 2810 and an innersurface of a renal artery or a renal ostium at a treatment site canthermally insulate portions of the renal artery or the renal ostiumclosest to the non-protruding portion from cryogenic temperatures withinthe balloon 2806. For example, frozen or liquid blood within this spacecan provide thermally insulation.

Balloons having different shapes can facilitate certain treatmentobjectives related to cryogenic renal-nerve modulation. For example,helical shapes can facilitate a desirable localized or overall treatmentpattern. FIG. 29 illustrates a portion of a cryotherapeutic device 2900including a cooling assembly 2902 at a distal portion 2904 of anelongated shaft 2906 defining an exhaust passage. The distal portion2904 can have a step 2907, an exit hole 2908, and an exhaust port 2909.The cooling assembly 2902 can include an applicator 2910 with a helicalballoon 2911 that defines an expansion chamber and has a balloonproximal portion 2912 and a balloon distal portion 2914. The balloonproximal portion 2912 has minor fluid connection with the exhaustpassage through the exit hole 2908. The balloon distal portion 2914 isattached to the outside surface of the distal portion 2904 around theexhaust opening 2909, thereby fluidly connecting the helical balloon2911 to the exhaust passage. The helical balloon 2911 is wrapped aroundthe distal portion 2904 (e.g., the distal portion 2904 can define acentral axis of the helical balloon 2911). The device 2900 can furtherinclude a supply tube 2916 defining a supply lumen and having a mainportion 2918 extending along the length of the shaft 2906 and an angleddistal portion 2920 exiting the shaft 2906 through the exit hole 2908.The cooling assembly 2902 also can include an orifice 2922 at the distalend of the angled distal portion 2920. The supply tube 2916 and theorifice 2922 can be configured to direct expansion of refrigerant intothe balloon proximal portion 2912 in a direction generally correspondingto a longitudinal orientation of the balloon proximal portion 2912. Whenthe cooling assembly 2902 is in a deployed state, refrigerant can flowfrom the balloon proximal portion 2912 to the balloon distal portion2914 and then proximally along the exhaust passage. Upon reaching theballoon distal portion 2914, the refrigerant can have exhausted some,most, or all of its capacity for cryogenic cooling.

FIG. 30 illustrates a portion of a cryotherapeutic device 3000 thatdiffers from the device 2900 of FIG. 29 primarily with respect to arefrigerant flow direction. The device 3000 includes a cooling assembly3002 at a distal portion 3004 of an elongated shaft 3006 defining anexhaust passage. The distal portion 3004 can have a step 3007, and thecooling assembly 3002 can include an applicator 3008 having a helicalballoon 3014 that defines an expansion chamber and has a balloonproximal portion 3016 and a balloon distal portion 3018. The balloonproximal portion 3016 can be attached to an outside surface of thedistal portion 3004 proximate a distal end of the distal portion 3004,thereby fluidly connecting the helical balloon 3014 to the exhaustpassage. The device 3000 can further include a supply tube 3019 having acurved distal portion 3020. The helical balloon 3014 can be wrappedaround the supply tube 3019 (e.g., the supply tube 3019 can define acentral axis of the helical balloon 3014). The supply tube 3019 canextend along the length of the shaft 3006, out of the shaft, out of theballoon proximal portion 3016, along a central axis of the helicalballoon 3014, and into the balloon distal portion 3018. The balloondistal portion 3016 can be sealed around the supply tube 3019 and atleast partially attached to the curved distal portion 3020. The coolingassembly 3002 can further include an orifice 3021 fluidly connecting thesupply tube 3019 to the balloon distal portion 3018. The supply tube3019 and the orifice 3021 can be configured to direct expansion ofrefrigerant into the balloon distal portion 3018 in a directiongenerally corresponding to a longitudinal orientation of the balloondistal portion 3018. When the cooling assembly 3002 is in a deployedstate, refrigerant can flow from the balloon distal portion 3018 to theballoon proximal portion 3016 and then proximally along the exhaustpassage.

FIG. 31 illustrates a portion of a cryotherapeutic device 3100 similarto the device 3000 of FIG. 30 except with regard to a helical balloonshape. The device 3100 includes a cooling assembly 3102 at a distalportion 3104 of an elongated shaft 3106 defining an exhaust passage. Thedistal portion 3104 can have a step 3108, and the cooling assembly 3102can include an applicator 3110 having a helical balloon 3112 thatdefines an expansion chamber and has a balloon proximal portion 3114 anda balloon distal portion 3116. The balloon proximal portion 3114 can beattached to an outside surface of the distal portion 3104 proximate adistal end of the distal portion 3104, thereby fluidly connecting thehelical balloon 3112 to the exhaust passage. The device 3100 can furtherinclude a supply tube 3117 having an angled distal portion 3118 Thehelical balloon 3112 can be wrapped around the supply tube 3117 but alsoradially spaced apart from the supply tube 3117. The supply tube 3117can extend along the length of the shaft 3106, out of the shaft 3106,out of the balloon proximal portion 3114, along a central axis of thehelical balloon 3112, and into the balloon distal portion 3116. Theballoon distal portion 3116 can be sealed around the supply tube 3117.The cooling assembly can further include an orifice 3119 fluidlyconnecting the supply tube 3117 to the balloon distal portion 3116. Whenthe cooling assembly 3102 is in a deployed state, refrigerant can flowfrom the balloon distal portion 3116 to the balloon proximal portion3114 and then proximally along the exhaust passage. The wide helicaldiameter of the helical balloon 3112 can facilitate partial occlusion.For example, when the cooling assembly 3102 is in the deployed state,the cooling assembly 3102 can define a flow path (e.g., a blood flowpath) between an outside surface of the supply tube 3117 and the helicalballoon 3112.

FIGS. 32A-32B illustrate a portion of a cryotherapeutic device 3200 thatcan have a complex shape corresponding to a shaping member, such as ashaping member having a shape memory. As discussed above, balloons incryotherapeutic devices configured in accordance with severalembodiments of the present technology can move from being at leastpartially collapsed when a corresponding cooling assembly is in adelivery state, to being at least partially expanded when the coolingassembly is in a deployed state. When expanded in the deployed state,complex balloons can have pre-defined shapes (e.g., integral shapesmolded or otherwise incorporated into the balloon) or shapescorresponding to separate shaping structures. The cryotherapeutic device3200 shown in FIGS. 32A-32B includes a cooling assembly 3202 at a distalportion 3204 of an elongated shaft 3206 defining an exhaust passage. Thedistal portion 3204 can have a step 3207, and the cooling assembly 3202can include an applicator 3208. The device 3200 can further include anelongated shaping member 3210 and a supply tube 3212 having an angleddistal portion 3214. The applicator 3208 can include a balloon 3216 witha distal seal 3217. The balloon 3216 can extend around the elongatedshaping member 3210 and can define an expansion chamber. The distal seal3217 can be a flattened portion of the balloon 3216 at which walls ofthe balloon 3216 are sealed together (e.g., thermally and/or withadhesive). Balloons configured in accordance with several otherembodiments of the present technology can have another type of closeddistal end. As discussed above, balloons can be closed aroundstructures, such as guide members and/or supply tubes. Balloons also canbe closed around plugs. Furthermore, balloons can have integral closeddistal ends. For example, balloons can be molded (e.g., dip molded) withintegral closed distal ends.

The shaping member 3210 can be configured to have a generally linearconfiguration when the cooling assembly 3202 is in a delivery state anda curvilinear configuration when the cooling assembly 3202 is in adeployed state. The cooling assembly 3202 can also include an orifice3218 at the distal end of the angled distal portion 3214. The supplytube 3212 and the orifice 3218 can be configured to direct expansion ofrefrigerant into the balloon 3216 in a direction generally correspondingto a longitudinal orientation of the balloon 3216 proximate the orifice3218. As shown in FIG. 32A, the balloon 3216 has a shape in the deployedstate at least partially corresponding to the curvilinear configurationof the shaping member 3210. The illustrated curvilinear configuration isgenerally helical, but also could be another shape, such as a serpentineshape. The shaping member 3210 can have a shape memory (e.g., a one-wayshape memory or a two-way shape memory) and can include a shape-memorymaterial, such as a nickel-titanium alloy (e.g., nitinol). Shape memorycan allow the shaping member 3210 and the balloon 3216 to move into apre-selected configuration (e.g., a curved, curvilinear, helical, orserpentine configuration) in the deployed state. The configuration canbe selected, for example, to allow the applicator 3208 to apply adesirable localized or overall treatment pattern. Similarly, the helicalshape shown in FIG. 32A and other shapes can be selected to provide alevel of occlusion at a treatment site, such as partial occlusioninstead of full occlusion. Shape-memory materials can lose some or allof their shaping properties when exposed to cryogenic temperatures.Cooling assemblies 3202 configured in accordance with severalembodiments of the present technology can include balloons 3216 thatmove into a pre-selected configuration corresponding to a shape of ashaping member 3210 before cryogenic cooling or during initial cryogeniccooling. When the cryogenic cooling causes the shaping member 3210 tolose some or all of its shaping properties, cryo-adhesion between theballoon 3216 and external material (e.g., blood and/or tissue) can causethe balloon 3216 to maintain its pre-selected configuration at leastuntil the cryo-adhesion ends.

In the embodiment illustrated in FIGS. 32A-32B, the shaping member 3210is shown generally centered within the balloon, i.e., the balloon 3216is generally uniformly expanded around the shaping member 3210.Alternatively, the shaping member 3210 can have a different positionwithin the balloon 3216 when the cooling assembly 3202 is in thedeployed state. For example, the shaping member 3210 can be near aninner surface of the balloon 3216. When the shaping member 3210 isspaced apart from walls of the balloon 3216, the balloon 3216 candissipate pressure against a renal artery or renal ostium. As shown inFIG. 32A, the shaping member 3210 can extend through the distal seal3217. Alternatively, the shaping member 3210 can be not attached to theballoon 3216 and/or terminate at a portion of the balloon 3216 proximalto the distal seal 3217. Furthermore, a distal portion of the shapingmember 3210 can be configured to be spaced apart from a renal artery orrenal ostium when the cooling assembly 3202 is in the deployed state. Insome embodiments, the balloon 3216 is configured to generally uniformlyexpand around the shaping member 3210 without any internal supportstructures. Alternatively, the balloon 3216 can include an internalstructure (e.g., webbing) extending across an inner diameter of theballoon 3216 and the shaping member 3210 can be attached to the internalstructure at a position spaced apart from inner surfaces of the balloon3216. The internal structure, for example, can be a partition betweenseparate balloons (e.g., as discussed below with reference to FIGS.45A-46). In some embodiments, the cooling assembly includes a structureextending along a central axis of the balloon 3216 in the deployedstate. For example, the distal portion 3204 can extend along the centralaxis of the balloon 3216 in the deployed state and the balloon 3216 andthe shaping member 3210 can connect to a lateral opening of the distalportion 3204. As another example, the distal portion 3204 can include areduced-diameter extension extending along the central axis of theballoon 3216 and another opening separate from the reduced-diameterextension fluidly connecting the balloon 3216 to the exhaust passage. Astructure extending along the central axis of the balloon 3216 caninclude a lumen (e.g., a lumen configured to receive a guide wire or acontrol wire), a protection device (e.g., a filter), and/or a monitoringdevice (e.g., a thermocouple or a pressure transducer).

The device 3200 can be modified for use in non-cryotherapeuticapplications. For example, the supply tube 3212 can be removed and thedevice 3200 can be used in other applications that benefit from lessthan full occlusion at a treatment site. In both renal-neuromodulationapplications and other applications, the balloon 3216 can benon-occlusive in the deployed state, e.g., a blood flow path can beformed along a central axis of the balloon 3216. In somenon-cryotherapeutic applications, the distal portion 3204 can support astructure configured to execute a treatment (e.g., a thrombectomy)within a vessel while the balloon 3216 anchors the device 3200 to avessel wall. In these and other embodiments, the balloon 3216advantageously can maintain the distal portion 3204 at a centralposition within a vessel.

FIGS. 33A-33D illustrate a portion of a cryotherapeutic device 3300 thatcan have a pre-defined curved shape in a deployed configuration. Thedevice 3300 includes a cooling assembly 3302 at a distal portion 3304 ofan elongated shaft 3306 defining an exhaust passage. The distal portion3304 can have a step 3307, and the cooling assembly 3302 can include anapplicator 3308 with a balloon 3310 that can define an expansionchamber. The balloon 3310 can have a balloon proximal portion 3312, aballoon middle portion 3314, and a balloon distal portion 3316. Thedevice 3300 further includes a supply tube 3318 extending along theshaft 3306, and the cooling assembly 3302 can have an orifice 3320 atthe distal end of the supply tube 3318 and within the balloon proximalportion 3312. When the cooling assembly 3302 is in a deployed state, theballoon 3310 is curved along its length and has a generally concavefirst wall 3322 (shown as a lower portion of the balloon in FIG. 33A)and a generally non-concave (e.g., convex) second wall 3324 (shown as anupper portion of the balloon in FIG. 33A).

The balloon proximal portion 3312, the balloon middle portion 3314, andthe balloon distal portion 3316 can be configured to contact partiallycircumferential portions of a renal artery or a renal ostium. Forexample, the balloon middle portion 3314 can be configured to contact arenal artery or a renal ostium generally along the second wall 3324 andgenerally not along the first wall 3322 when the cooling assembly 3302is in a deployed state. The balloon proximal portion 3312 and theballoon distal portion 3316, for example, can be configured to contact arenal artery or a renal ostium generally along the first wall 3322 andgenerally not along the second wall 3324 when the cooling assembly 3302is in the deployed state. Due to this uneven pattern of contact, thecurved shape of the balloon 3310 can facilitate a desirable localized oroverall treatment pattern.

As best seen in FIGS. 33B-33C, the balloon 3310 can include areduced-elasticity portion 3326 along the first wall 3322 at the balloonmiddle portion 3314. In the illustrated embodiment, thereduced-elasticity portion 3326 can be a thicker portion of the balloon3310. As shown in FIG. 33D, the balloon 3310 can be partially collapsedwhen the cooling assembly 3302 is in the delivery state so as to fitwithin a delivery sheath 3328. When the cooling assembly 3302 is in thedelivery state, the reduced-elasticity portion 3326 can retain somecurvature. Alternatively, the reduced-elasticity portion 3326 can begenerally flat. When the cooling assembly 3302 is in a deployed state,portions of the balloon 3310 other than the reduced elasticity portion3326, particularly portions of the balloon 3310 along the second wall3324 at the balloon middle portion 3314 can be configured to expand(e.g., compliantly expand) to a greater degree than thereduced-elasticity portion 3326. In several embodiments, thereduced-elasticity portion 3326 is generally non-compliant and a portionof the balloon 3310 along the second wall 3324 at the balloon middleportion 3314 is generally compliant. Restriction associated with thereduced-elasticity portion 3326 can facilitate curvature of the balloon3310 when the cooling assembly 3302 is in the deployed state. Thereduced-elasticity portion 3326 can be configured to be recessedrelative to a renal artery or a renal ostium when the cooling assembly3302 is in the deployed state and, correspondingly, not encompass aheat-transfer portion having a heat-transfer rate sufficient to causetherapeutically-effective renal nerve modulation. In addition toreducing elasticity, the thickness of the reduced-elasticity portion3326 can reduce its thermal conductivity, which can promote improvecooling efficiency and/or further facilitate a desirable localized oroverall treatment pattern.

FIG. 34 illustrates a portion of a cryotherapeutic device 3400 similarto the device 3300 of FIGS. 33A-33D except having a different supportconfiguration. The device 3400 includes a cooling assembly 3402 havingan applicator 3404 with a balloon 3406 defining an expansion chamber.The cooling assembly 3402 also includes an elongated support member 3408having a curved distal end 3410. The elongated support member 3408 andother support members described herein can help balloons move with acorresponding cooling assembly as the cooling assembly moves between adelivery state and a deployed state. For example, the elongated supportmember 3408 can help to prevent the balloon 3406 from becoming stuck ortwisted during treatment. Optionally, elongated support members can beattached to distal portions of corresponding balloons. This can beuseful, for example, to maintain a balloon in an elongatedconfiguration.

FIGS. 35A-35B illustrate a portion of a cryotherapeutic device 3500 inwhich interaction with a guide member at least partially causes acomplex balloon shape. In several other embodiments, a complex balloonis at least partially shaped through interaction with anothercryotherapeutic-device component (e.g., a shaft or a supply tube). Thedevice 3500 shown in FIGS. 35A-35B includes a cooling assembly 3502 at adistal portion 3504 of an elongated shaft 3506 defining an exhaustpassage. The device 3500 can include an elongated guide member 3508 anda supply tube 3512, and the cooling assembly 3502 can include an orifice3514 at the distal end of the supply tube 3512. The cooling assembly canfurther include an applicator 3510 with a balloon 3516 that can definean expansion chamber and can have a balloon proximal portion 3518, aproximal integral neck 3520 attached to the distal portion 3504, and adistal integral neck 3522 attached to the guide member 3508. The balloon3516 can also have a constrained longitudinal portion 3524 (FIG. 35B)and an expandable longitudinal portion 3526 (FIG. 35B). The constrainedlongitudinal portion 3524 can be at least partially attached to theguide member 3508. For example, from the distal integral neck 3522 tothe balloon proximal portion 3518, an internal surface of the balloon3516 can be attached to the guide member 3508. The expandablelongitudinal portion 3526 can be spaced apart from the guide member 3508when the cooling assembly 3502 is in a deployed state. Thepartially-constrained shape of the balloon 3516 can be useful tofacilitate a desirable localized or overall treatment pattern.Furthermore, the constrained longitudinal portion 3524 can define atleast a portion of a longitudinal flow path (e.g., a blood flow path)around the balloon 3516. This can be useful, for example, to facilitatea level of occlusion at a treatment site, such as partial occlusioninstead of full occlusion.

FIG. 36 illustrates a cryotherapeutic device 3600 similar to thecryotherapeutic device 3500 of FIGS. 35A-35B, except having a differentpattern of attachment between a balloon and a guide member. FIG. 36 canbe considered as a substitute for FIG. 35B to illustrate a separateembodiment in which all elements of the cryotherapeutic device 3500shown in FIGS. 35A-35B are similar except for those shown differently inFIG. 36 relative to FIG. 35B. The cryotherapeutic device 3600 includesan elongated guide member 3602 and a balloon 3604 having radially spacedapart constrained longitudinal portions 3506 and radially spaced apartexpanded longitudinal portions 3508. Although FIG. 36 shows twoconstrained longitudinal portions 3606 and two expanded longitudinalportions 3608, a greater number of constrained longitudinal portions3606 and/or expanded longitudinal portions 3608 can be formed forexample, by attaching the balloon 3604 to the guide member 3602 at adifferent number of radial segments of the guide member 3602.Furthermore, the distribution of constrained longitudinal portions 3606and expanded longitudinal portions 3608 can be symmetrical orasymmetrical (e.g., along an axis parallel to the length of the guidemember 3602).

FIG. 37 illustrates a portion of a cryotherapeutic device 3700 includinga balloon having a loop shape. The device 3700 includes a coolingassembly 3702 at a distal portion 3704 of an elongated shaft 3706defining an exhaust passage, as well as a supply tube 3708. The coolingassembly 3702 includes an orifice 3710 at the distal end of the supplytube 3708, and an applicator 3712 with a balloon 3714 having a firstballoon segment 3716 and a second balloon segment 3718. The firstballoon segment 3716 has a first proximal portion 3720 and a firstdistal portion 3722. The second balloon segment 3718 has a secondproximal portion 3724 and a second distal portion 3726. The firstballoon distal portion 3722 is fluidly connected to the second distalportion 3726. When the cooling assembly 3702 is in the deployed state,refrigerant can flow from the first proximal portion 3720, to the firstdistal portion 3722, and then to the second distal portion 3726. Uponreaching the second distal portion 3726, the refrigerant can haveexhausted some, most, or all of its capacity for cryogenic cooling.Accordingly, the second balloon segment 3718 can serve primarily toexhaust refrigerant from the first distal portion 3722 and have aheat-transfer portion with a heat-transfer rate lower than aheat-transfer rate of a heat-transfer portion of the firstballoon-segment 3716. In several alternative embodiments, the firstballoon segment 3716 and the second balloon segment 3718 are separateballoons with a fluid connection at their distal ends. In anotherembodiment, the first and second balloon segments can be portions of asingle balloon that is folded. Similar to non-cooling balloons discussedbelow, the second balloon segment 3718 can thermally insulate a portionof a renal artery or a renal ostium at a treatment site from cryogenictemperatures within the first balloon segment 3716. This can be useful,for example, to facilitate a desirable localized or overall treatmentpattern.

Multiple Balloons

FIGS. 38-51 illustrate several embodiments of cryotherapeutic devicesthat include multiple balloons that can facilitate one or more treatmentobjectives related to cryogenic renal-nerve modulation, such as adesirable localized or overall treatment pattern, sizing, and fullocclusion. In cryotherapeutic devices configured in accordance withseveral embodiments of the present technology, a primary balloonconfigured to generate or deliver therapeutically effective cooling forrenal nerve modulation (e.g., including a primary heat-transfer portion)can be used in conjunction with a secondary balloon configured toprevent or inhibit therapeutically effective cooling temperatures atselected locations. In several embodiments, a secondary balloon includesa secondary heat-transfer portion. A secondary balloon, for example, canbe warming, thermally-insulative, non-cooling, or have a low-level ofcooling. Alternatively, several embodiments include multiple balloonsthat include primary heat-transfer portions with or without a secondaryballoon.

FIGS. 38A-38B illustrate a portion of a cryotherapeutic device 3800 thatcan have multiple primary balloons. The device 3800 includes a coolingassembly 3802 at a distal portion 3804 of an elongated shaft 3806defining an exhaust passage. The distal portion 3804 can have a step3807, and the device 3800 can include an elongated guide member 3808 anda supply tube 3810. The cooling assembly 3802 can include an orifice3811 at the distal end of the supply tube 3810 and an applicator 3812having elongated balloons 3814 positioned generally parallel to a lengthof the cooling assembly 3802. The balloons 3814 have a shared proximalportion 3816 and are otherwise circumferentially distributed around theguide member 3808. The orifice 3811 is within the shared proximalportion 3816 and the balloons 3814, in conjunction with the sharedproximal portion 3816, can define expansion chambers. When the coolingassembly 3802 is in a deployed state, refrigerant expanded from thesupply tube 3810 can enter the shared proximal portion 3816 andcirculate within the balloons 3814 to cause expansion thereof andcooling. Refrigerant can exit the balloons 3814 also through the sharedproximal portion 3816 and flow proximally along the exhaust passage. Theballoons 3814 can be configured to contact spaced-apart portions (e.g.,spaced-apart longitudinal portions) of a renal artery or a renal ostiumat a treatment site. This can be useful to facilitate a desirablelocalized or overall treatment pattern. Furthermore, space between theballoons 3814 can define at least a portion of a longitudinal flow path(e.g., a blood flow path) around the balloons 3814. This can be useful,for example, to facilitate a level of occlusion at a treatment site,such as partial occlusion instead of full occlusion.

FIGS. 39A-39C illustrate a portion of a cryotherapeutic device 3900 thatcan have multiple balloons having different levels of cooling. Thedevice 3900 includes a cooling assembly 3902 at a distal portion 3904 ofan elongated shaft 3906, an elongated guide member 3907, and a pluralityof supply tubes (individually identified as 3908 a-d). The coolingassembly 3902 can include a plurality of orifices (individuallyidentified as 3910 a-d) at the distal ends of the supply tubes 3908 a-d,and an applicator 3912 including a plurality of elongated balloons(individually identified as 3914 a-d in FIGS. 39A and 39C). The balloons3914 a-d are circumferentially distributed around the guide member 3907and individually include proximal necks 3916 (FIG. 39A) that can fluidlyconnect the balloons 3914 a-d to the exhaust passage. The orifices 3910a, 3910 d have larger free-passage areas than the orifices 3910 b, 3910c. Similarly, the supply tubes 3908 a, 3908 d have smaller free-passageareas than the supply tubes 3908 b, 3908 d. The balloons 3914 a-d aregenerally equal in size and have generally equal internal and externalsurface areas. A ratio of orifice and/or supply tube free-passage areato internal surface area can be greater for the balloons 3914 a, 3914 dthan for the balloons 3914 b, 3914 c. This can cause differentialcooling within the balloons 3914 a, 3914 d relative to the balloons 3914b, 3914 c. For example, the balloons 3914 a, 3914 d can be configured tocirculate gaseous refrigerant at a lower temperature than the balloons3914 b, 3914 c. In addition or alternatively, the balloons 3914 a, 3914d can be configured for generally surface-area limited cooling when thecooling assembly 3902 is in the deployed state, while the balloons 3914b, 3914 c are configured for generally refrigerant-limited cooling whenthe cooling assembly 3902 is in the deployed state. Providing somecooling (e.g., low-level cooling, such as cooling insufficient forcryogenic renal nerve modulation) to tissue near an area targeted fortherapeutically-effective renal nerve modulation can be useful, forexample, to reduce heat-gain from surrounding tissue at the areatargeted for therapeutically-effective renal nerve modulation. The useof multiple balloons also can facilitate a desirable localized oroverall treatment pattern and/or a desired level of occlusion at atreatment site, such as partial occlusion instead of full occlusion.

FIG. 40 illustrates a cryotherapeutic device 4000 similar to thecryotherapeutic device 3900 of FIGS. 39A-39C, except having a differentmechanism for differential cooling. FIG. 40 can be considered as asubstitute for FIG. 39B to illustrate a separate embodiment in which allelements of the cryotherapeutic device 3900 shown in FIGS. 39A-39C aresimilar except for those shown differently in FIG. 40 relative to FIG.39B. The cryotherapeutic device 4000 includes a shaft 4002 havinginternal walls 4004 dividing the shaft 4002 into fluidly separateexhaust passages, and supply tubes 4006 individually within the exhaustpassages. The supply tubes 4006 have generally equal sizes and can haveorifices (not shown) having generally equal sizes. The cryotherapeuticdevice 4000 also includes a plurality of pressure regulators(individually identified as 4008 a-d) in fluid communication with theexhaust passages. The pressure regulators 4008 a-d can be configured tobe positioned outside the vasculature. Regulating back pressures withinthe exhaust passages can cause temperatures within correspondingballoons (not shown) to vary. For example, the pressure regulators 4008a, 4008 d can maintain a first back pressure in the correspondingexhaust passages and balloons, and the pressure regulators 4008 b, 4008c can maintain a second, different back pressure in the correspondingexhaust passages and balloons. In this way, differential cooling similarto the differential cooling described above with reference to the device3900 shown in FIGS. 39A-39C can be achieved.

FIG. 41 illustrates a portion of a cryotherapeutic device 4100 that canhave multiple helical balloons. The device 4100 includes a coolingassembly 4101 at a distal portion 4102 of an elongated shaft 4103defining an exhaust passage, a supply tube 4104, and a filler tube 4105.The cooling assembly 4101 can include a first supply orifice 4106, asecond supply orifice 4107, and a filler orifice 4108 at the distal endof the filler tube 4105. The cooling assembly 4101 also includes anapplicator 4109 having a plurality of helical balloons. In oneembodiment, the applicator 4109 includes a first helical balloon 4110having a first distal portion 4112 and a first proximal portion 4114, asecond helical balloon 4116 (shown stippled for clarity of illustration)having a second distal portion 4118 and a second proximal portion 4120,and a third helical balloon 4122 having a third distal portion 4124 anda third proximal portion 4126. The first and second supply orifices4106, 4107 can be fluidly connected to the first distal portion 4112 andthe third distal portion 4124, respectively, and the first and thirdhelical balloons 4110, 4122 can define expansion chambers. Thesecond-balloon proximal portion 4120 can be sealed around the fillertube 4107 and fluidly connected to the filler orifice 4108 and thesecond helical balloon 4116 can define a filler chamber. When thecooling assembly 4101 is in the deployed state, the second helicalballoon 4116 can be configured to be filled via the filler tube 4105.Refrigerant can expand into the first distal portion 4112 and the thirddistal portion 4124, and the first and third helical balloons 4110, 4122can provide primary cooling in separate helical patterns or a combinedhelical pattern. The second helical balloon 4116 can thermally insulateportions of a renal artery or a renal ostium from cryogenic cooling ofthe first and third helical balloons 4110, 4122. This can be useful, forexample, to facilitate a desirable localized or overall treatmentpattern. Furthermore, the interior space between the supply tube 4004and the first, second, and third helical balloons 4110, 4116, 4122 candefine at least a portion of a longitudinal flow path (e.g., a bloodflow path). This can be useful, for example, to facilitate a level ofocclusion at a treatment site, such as partial occlusion instead of fullocclusion.

FIG. 42 illustrates a portion of a cryotherapeutic device 4200 similarto the device 4100 shown in FIG. 41, but having modified supply andexhaust configurations in the helical balloons. The device 4200 includesa cooling assembly 4202 at a distal portion 4203 of an elongated shaft4204 defining an exhaust passage, an elongated guide member 4205, and asupply tube 4206. The cooling assembly 4202 can include a supply orifice4207 at the distal end of the supply tube 4206 and an applicator 4208having a plurality of helical balloons. In one embodiment, theapplicator 4208 includes a first helical balloon 4210 having a firstdistal portion 4212 and a first proximal portion 4214, a second helicalballoon 4216 (shown stippled for clarity of illustration) having asecond distal portion 4218 and a second proximal portion 4220, and athird helical balloon 4222 having a third distal portion 4224 and athird proximal portion 4226. The first distal portion 4212 and the thirddistal portion 4224 are fluidly connected to each other and to thesecond distal portion 4218. The first proximal portion 4214 and thethird proximal portion 4226 are fluidly connected to the exhaustpassage. When the cooling assembly 4202 is in the deployed state,refrigerant can expand into the second proximal portion 4220 and thesecond helical balloon 4216 can provide primary cooling in a helicalpattern. The first and third helical balloons 4210, 4222 can receiverefrigerant exhaust from the second distal portion 4218 and canthermally insulate portions of a renal artery or a renal ostium fromcryogenic cooling within the second helical balloon 4216. Relative tothe cryotherapeutic device 4200 shown in FIG. 41, the device 4100 can beuseful when less cooling and/or greater spacing between areas of primarycooling is desirable. In several other embodiments, different numbers ofhelical balloons that are warming, thermally-insulative, non-cooling, orhave a low-level of cooling are intertwined in various arrangements withhelical balloons configured to provide primary cooling, such as tofacilitate a desirable localized or overall treatment pattern.

FIGS. 43A-43C illustrate a portion of a cryotherapeutic device 4300 thatcan include balloons that are movable relative to other portions of acooling assembly. The device 4300 includes a cooling assembly 4301 at adistal portion 4302 of an elongated shaft 4303 defining an exhaustpassage, as well as an elongated shaping member 4304, a first supplytube 4305, and a second supply tube 4306. The distal portion 4302 canhave a step 4307, and the cooling assembly 4301 can include a firstorifice 4308 at the distal end of the first supply tube 4305, and asecond orifice 4309 at the distal end of the second supply tube 4306.The cooling assembly 4301 further includes an applicator 4310 with afirst elongated balloon 4311 defining a first expansion chamber and asecond elongated balloon 4312 defining a second expansion chamber. Thefirst balloon 4311 has a first proximal portion 4314, a first middleportion 4315, and a first distal portion 4316. The second balloon 4312has a second proximal portion 4318, a second middle portion 4319, and asecond distal portion 4320. The first and second balloons 4311, 4312have inner sides 4322 closest to the shaping member 4304 and outer sides4324 opposite the inner sides 4322. The first distal portion 4316 andthe second distal portion 4320 are attached to the shaping member 4304.In several embodiments, the shaping member 4304 also defines a guidelumen through which a guide wire can be threaded.

As shown in FIG. 43C, when the cooling assembly 4301 is in the deployedstate, retracting the shaping member 4304 relative to the shaft 4303 cancause the first middle portion 4315 and the second middle portion 4319to laterally move away from the shaping member 4304. A portion of thefirst middle portion 4315 and/or a portion of the second middle portion4319 can be weakened (e.g., creased, heat-treated to cause weakening,and/or thinned) or otherwise configured to define a preferential bendposition. As shown in FIG. 43C, after the shaping member 4304 hasretracted the inner sides 4322 of the first middle portion 4315 and thesecond middle portion 4319 are generally concave along their lengths,while the outer sides 4324 of the first middle portion 4315 and thesecond middle portion 4319 are generally convex along their lengths.Controlled deflection of balloons can be particularly useful, forexample, to facilitate sizing with low risk of applying excessiveexpansive pressure to a renal artery or a renal ostium. Controlleddeflection can be particularly useful when one or more balloons of anapplicator are generally non-compliant and/or achieving sizing throughcompliant expansion is not practical.

FIGS. 44A-44C illustrate a portion of a cryotherapeutic device 4400similar to the cryotherapeutic device 4300 shown in FIGS. 43A-43B, buthaving a greater number of elongated balloons and including a secondaryballoon. The device 4400 includes a distal portion 4402 of an elongatedshaft 4404 having a step 4405 and defining an exhaust passage, a coolingassembly 4406 at the distal portion 4402, and an elongated shapingmember 4408. The shaping member 4304 can be solid or can define a lumen,such as a guide lumen through which a guide wire can be threaded. Thedevice 4400 further includes a first supply tube 4410, a second supplytube 4414, a third supply tube (not shown), and a filler tube 4416. Thecooling assembly 4406 can include a first supply orifice 4418 at thedistal end of the first supply tube 4410, a second supply orifice 4420at the distal end of the second supply tube 4414, a third orifice (notshown) at the distal end of the third supply tube, and a filler orifice4422 at the distal end of the filler tube 4416. The cooling assembly4406 also includes an applicator 4424 with an elongated first balloon4426 defining a first expansion chamber, an elongated second balloon4428 defining a second expansion chamber, an elongated third balloon4430 (FIG. 44B) defining a third expansion chamber, and an elongatedfourth balloon 4432 defining a filler chamber. The first, second, andthird balloons 4426, 4428, 4430 are fluidly connected to the first,second, and third supply orifices 4418, 4420. The fourth balloon isfluidly connected to the filler orifice 4422 and is sealed around thefiller tube 4416. The first, second, third, and fourth balloons 4426,4428, 4430, 4432 are attached to the shaping member 4408 such that, asshown in FIG. 44C, when the cooling assembly 4406 is in a deployedstate, retracting the shaping member 4408 relative to the shaft 4404causes the applicator 4424 to laterally expand. The first, second, andthird balloons 4426, 4428, 4430 can have heat-transfer portions withheat-transfer rates sufficient to cause therapeutically-effective renalnerve modulation. The first, second, and third balloons 4426, 4428, 4430can be configured to provide primary cooling. The fourth balloon 4432can be a secondary balloon. In several other embodiments, a differentnumber of primary balloons with or without secondary balloons can beincluded in a similar configuration to the configurations of thecryotherapeutic device 4300 shown in FIGS. 43A-43B and thecryotherapeutic device 4400 shown in FIGS. 44A-44C. In addition tosizing, these configurations can facilitate other treatment objectives,such as a desirable localized or overall treatment pattern

FIGS. 45A-45B illustrate a portion of a cryotherapeutic device 4500including a primary balloon and a secondary balloon that can havedifferent compositions. The device 4500 includes a cooling assembly 4502at a distal portion 4504 of an elongated shaft 4506 defining an exhaustpassage, a supply tube 4508, and a filler tube 4509. The coolingassembly 4502 includes a supply orifice 4510 at the distal end of thesupply tube 4508, and a filler orifice 4514 at the distal end of thefiller tube 4509. The cooling assembly 4502 also includes an applicator4516 with a first balloon 4518 that defines an expansion chamber and asecond balloon 4520 that can define a filler chamber. The first balloon4518 has a proximal neck 4522 within the distal portion 4504 fluidlyconnecting the first balloon 4518 to the exhaust passage. The secondballoon is sealed around the filler tube 4509 and fluidly connected tothe filler orifice 4514. When the cooling assembly 4502 is in a deployedstate, the first balloon 4518 can be configured to deliver primarycooling and the second balloon 4520 can be a secondary balloon.

In several embodiments, the first balloon 4518 has a lower level ofcompliance and/or elasticity than the second balloon 4520. For example,the first balloon 4518 can be generally non-compliant and the secondballoon can be generally compliant. Additionally, the first balloon 4518can be non-compliant and the second balloon can be compliant.Non-compliant materials typically have higher strength (e.g., higherpressure ratings) than compliant materials. For this and/or otherreasons, generally compliant materials can be well suited for balloonsconfigured to receive expanded refrigerant directly from an orificeand/or to apply therapeutically effective cooling for renal nervemodulation. Generally compliant materials can be well suited forexpanding to different sizes to accommodate renal arteries and renalostiums having different cross-sectional dimensions. The device 4500shown in FIGS. 45A-45B and several other cryotherapeutic-devicecomponents described herein can be configured to take advantage of thedifferent properties of both non-compliant and compliant materials.FIGS. 45B and 45C are cross-sectional views of the device 4500 sized tofit within renal arteries or renal ostiums of different cross-sectionaldimensions. The first balloon 4518 has generally the same size in bothFIG. 45B and FIG. 45C. The second balloon 4520, however, is compliantlyexpanded to a greater degree in FIG. 45C than in FIG. 45B. Even with thegenerally non-compliant expansion of the first balloon 4518, thevariable, compliant expansion of the second balloon 4520 can move thefirst balloon into contact with an inner surface of a renal artery or arenal ostium. Compliant expansion of the second balloon 4520 can becarefully controlled via the filler tube 4509 to prevent excessiveexpansive forces on the renal artery or the renal ostium.

The enlargement in FIG. 45B-1 shows a partition 4524 that includes alayer of non-compliant material 4526 and a layer of compliant material4528. The layer of non-compliant material 4526 can be a portion of thefirst balloon 4518 and the layer of compliant material 4528 can be aportion of the second balloon 4520. In one embodiment, the first balloon4518 and the second balloon 4520 can be attached together at thepartition 4524, but in other embodiments the first and second balloon4518 and 4520 are not attached to each other.

FIG. 46 illustrates a cryotherapeutic device 4600 similar to thecryotherapeutic device 4500 of FIGS. 45A-45C, except having a differentpartition. FIG. 46 can be considered as a substitute for FIG. 45B toillustrate a separate embodiment in which all elements of thecryotherapeutic device 4500 shown in FIGS. 45A-45C are similar exceptfor those shown differently in FIG. 46 relative to FIG. 45B. Thecryotherapeutic device 4600 includes a first balloon 4602, a secondballoon 4604, and a partition 4606 between the first balloon 4602 andthe second balloon 4604. As shown in the enlargement in FIG. 46-1, thepartition 4606 includes a single layer, which can be a non-compliantlayer of the first balloon. In another embodiment, the partition 4606can include a single layer that is a compliant layer of the secondballoon 4604. To construct the device 4600, a generally compliantballoon portion (e.g., an incomplete balloon) can be attached to agenerally non-compliant balloon so as to form a generally compliantballoon having a chamber at least partially defined by a portion of thegenerally non-compliant balloon. In cross section, as shown in FIG. 46,the first balloon 4602 can be a generally D-shaped balloon and thesecond balloon 4604 can be a generally C-shaped balloon attached to agenerally D-shaped balloon.

Cryotherapeutic devices configured in accordance with severalembodiments of the present technology can include helical primaryballoons and non-helical secondary balloons. FIG. 47 illustrates aportion of a cryotherapeutic device 4700 including a cooling assembly4702 at a distal portion 4704 of an elongated shaft 4706 defining anexhaust passage. The device 4700 also includes a supply tube 4707. Thecooling assembly 4702 includes an applicator 4708 with a helical firstballoon 4710 having a first proximal portion 4712 and a first distalportion 4714 and defining an expansion chamber. The supply tube 4707 canextend into the first proximal portion 4712, and the cooling assembly4702 can have an orifice 4718 at the distal end of the supply tube 4707within the first proximal portion 4712. The first proximal portion 4712is sealed around the supply tube 4707. The cooling assembly 4702 canfurther include a second balloon 4720 having a second proximal portion4722 and a second distal portion 4724 and defining an exhaust chamber.The second distal portion 4724 can be fluidly connected to the firstdistal portion 4714, and the first balloon 4710 can wrap around thesecond balloon 4720. The second proximal portion 4722 can be fluidlyconnected to the exhaust passage. When the cooling assembly 4702 is in adeployed state, refrigerant can flow from the first proximal portion4712 to the first distal portion 4714 and then proximally through thesecond balloon 4720. Back pressure from the refrigerant can cause thesecond balloon 4720 to expand (e.g., compliantly expand), which cancause a helical diameter of the first balloon 4710 to increase. This canbe useful, for example, to facilitate sizing. In addition, the helicalshape of the first balloon 4710 can be useful, for example, tofacilitate a desirable localized or overall treatment pattern.

FIGS. 48A-48B illustrate a portion of a cryotherapeutic device 4800having a helical primary balloon and a non-helical secondary balloon ina different configuration. The device 4800 includes a cooling assembly4802 at a distal portion 4804 of an elongated shaft 4806 defining anexhaust passage. The distal portion 4804 can have a step 4807, and thecooling assembly 4802 can include an applicator 4808 with a helicalfirst balloon 4810 that defines an expansion chamber and has a firstproximal portion 4812 and a first distal portion 4814. The device 4800also can include a supply tube 4816 extending into the first proximalportion 4812, and the cooling assembly 4802 can have an orifice 4818 atthe distal end of the supply tube 4816 within the first proximal portion4812. The first proximal portion 4812 is sealed around the supply tube4816. The cooling assembly 4802 can further include a second balloon4820 having an integral proximal neck 4822 attached to the distalportion 4804. The second balloon 4820 can define an exhaust chamberconfigured to expand (e.g., compliantly expand) in response to backpressure from refrigerant exhausted from the first balloon 4810. Thefirst balloon 4810 can be attached to an internal surface of the secondballoon 4820. Expansion (e.g., compliant expansion) of the secondballoon 4820 can cause a helical diameter of the first balloon 4810 toincrease, such as to move a curved portion of the first balloon 4810closer to an inner surface of a renal artery or a renal ostium.Positioning the first balloon 4810 within the second balloon 4820 can beuseful, for example, to provide redundant containment of refrigerantwithin the vasculature.

FIG. 49 illustrates a portion of a cryotherapeutic device 4900 includinga helical primary balloon and a non-helical secondary balloon in anotherconfiguration. The device 4900 includes a cooling assembly 4902 at adistal portion 4904 of an elongated shaft 4905 defining an exhaustpassage. The distal portion 4904 can have a step 4906 and a plurality ofexhaust openings 4907. The cooling assembly 4902 can include anapplicator 4908 with a helical first balloon 4910 that defines anexpansion chamber and has a first proximal portion 4912 and a firstdistal portion 4914. The device 4900 also can include a supply tube 4916that extends into the first proximal portion 4912, and the coolingassembly 4902 can have an orifice 4918 at the distal end of the supplytube 4916. The first proximal portion 4912 can be sealed around thesupply tube 4916. The cooling assembly 4902 can further include a secondballoon 4920 positioned around the distal portion 4904 and having anintegral proximal neck 4922 attached to the distal portion 4904. Thefirst balloon 4910 can wrap around the second balloon 4920 and the firstdistal portion 4914 can be fluidly connected to the distal portion 4904distal of the second balloon 4920. When the cooling assembly 4902 is ina deployed state, the second balloon 4920 can be configured to passivelyreceive refrigerant from the exhaust passage through the exhaustopenings 4907 and can be configured to expand (e.g., compliantly expand)in response to back pressure from refrigerant exhausted from the firstballoon 4910. Expansion (e.g., compliant expansion) of the secondballoon 4920 can cause a helical diameter of the first balloon 4910 toincrease, which can cause a portion (e.g., a curved portion) of thefirst balloon 4910 to move closer to an inner surface of a renal arteryor a renal ostium.

FIG. 50 illustrates a portion of a cryotherapeutic device 5000 includinga helical primary balloon and a non-helical secondary balloon in anotherconfiguration. The device 5000 includes a cooling assembly 5002 at adistal portion 5003 of an elongated shaft defining an exhaust passage, afiller tube 5004, a filler orifice 5005 at the distal end of the fillertube 5004, and a supply tube 5006. The cooling assembly 5002 includes asupply orifice 5007 at the distal end of the supply tube 5006. Thesupply tube 5006 can include a corner 5008, such as an elbow, near thesupply orifice 5007. The cooling assembly 5002 further includes anapplicator 5009 with a helical first balloon 5010 that defines anexpansion chamber and has a first proximal portion 5011 and a firstdistal portion 5012. The cooling assembly 5002 can also include a secondballoon 5014 having a second proximal portion 5016 and a second distalportion 5018. The second proximal portion 5016 can be fluidly connectedto the filler orifice 5005 and sealed around the filler tube 5004. Thesecond distal portion 5018 can be sealed around the supply tube 5006,but fluidly separate from the supply tube 5024 and the first balloon5010. The first balloon 5010 can wrap around the second balloon 5014 andbe configured to receive refrigerant from the supply tube 5006 and toexhaust the refrigerant through the first proximal portion 5011 into theexhaust passage. The second balloon 5014 can be configured to receivefiller material from the filler tube 5004 and expand (e.g., compliantlyexpand) causing a helical diameter of the first balloon 5010 toincrease, which can cause a portion (e.g., a curved portion) of thefirst balloon 5010 to move closer to an inner surface of a renal arteryor a renal ostium.

FIG. 51 illustrates a portion of a cryotherapeutic device 5100 includinga helical primary balloon and a non-helical secondary balloon in anotherconfiguration. The device 5100 includes a cooling assembly 5101 at adistal portion 5102 of an elongated shaft 5103 defining an exhaustpassage, a supply tube 5106, and a filler tube 5108. The distal portion5102 can have a step 5104 and an exit hole 5105. The cooling assembly5101 can include a supply orifice 5107 at the distal end of the supplytube 5106, and a filler orifice 5109 at the distal end of the fillertube 5108. The cooling assembly 5101 can further include an applicator5110 with a helical first balloon 5111 that defines an expansion chamberand has a first proximal portion 5112 and a first distal portion 5114.The supply tube 5106 can extend from the exit hole 5105 and extend intothe first proximal portion 5112, and the first proximal portion 5112 canbe sealed around the supply tube 5106. The cooling assembly 5101 canfurther include a second balloon 5116 around the distal portion 5102 andhaving an integral proximal neck 5118 attached to the distal portion5102. The second balloon 5116 can be configured to receive fillermaterial from the filler tube 5108 and expand (e.g., compliantly expand)causing a helical diameter of the first balloon 5111 to increase, whichcan cause a portion (e.g., a curved portion) of the first balloon 5111to move closer to an inner surface of a renal artery or a renal ostium.

Proximal Secondary Balloons

A primary balloon and a secondary balloon can be longitudinally spacedapart along the length of a portion of a cryotherapeutic deviceconfigured in accordance with several embodiments of the presenttechnology. For example, a secondary balloon can be part of an occlusionmember configured to fully or partially occlude a renal artery and/or arenal ostium. FIGS. 52A-53 illustrate several embodiments ofcryotherapeutic devices that include proximal secondary balloons.

FIGS. 52A-52B illustrate a portion of a cryotherapeutic device 5200including a cooling assembly 5202 and an occlusion member 5204longitudinally spaced apart along an elongated shaft 5206 defining anexhaust passage. The shaft 5206 can have a first stepped-down portion5208, cooling-assembly exhaust portal 5209 at the first stepped-downportion 5208, a second stepped-down portion 5210, and occlusion-memberexhaust portals 5211 at the second stepped-down portion 5210. Thecooling assembly 5202 and the occlusion member 5204 can be positioned atthe first stepped-down portion 5208 and the second stepped-down portion5210, respectively. The device 5200 can include a supply tube 5212, andthe cooling assembly 5202 can have orifice 5213 at the distal end of thesupply tube 5212. The cooling assembly 5202 also can include anapplicator 5214 with a first balloon 5215 that defines an expansionchamber. The supply tube 5212 can angle out of the shaft 5206 and intothe first balloon 5215. The occlusion member 5204 can include a secondballoon 5216 defining an occlusion chamber. The second balloon 5216 canbe configured to passively receive refrigerant from the exhaust passagethrough the occlusion-member exhaust portal 5211 and can be configuredto expand (e.g., compliantly expand) in response to back pressure fromrefrigerant exhausted from the cooling assembly 5202. Both the coolingassembly 5202 and the occlusion member 5204 can be at least partiallycollapsible in a delivery state and are shown in FIGS. 52A-52B in anexpanded state and a deployed state, respectively. In the expandedstate, the occlusion member 5204 can have a cross-sectional dimensionconfigured to fully occlude a renal artery and/or a renal ostium.

As shown in FIG. 52B, the device 5200 can further include a firstelongated control member 5218, a second elongated control member 5220,and a control tube 5222 with a first distal branch 5224 and a seconddistal branch 5226. The shaft 5206 can further include a first distalattachment point 5228, a second distal attachment point 5230, and aflexing portion 5232 between the first stepped-down portion 5208 and thesecond stepped-down portion 5210. The first elongated control member5218 can extend along the control tube 5222, along the first distalbranch 5224, and attach to the first distal attachment point 5228. Thesecond elongated control member 5220 can extend along the control tube5222, along the second distal branch 5226, and attach to the seconddistal attachment point 5230. The device 5200 can be configured suchthat increasing or decreasing tension of the first control member 5218and/or the second control member 5220 can control deflection of theshaft 5206. The shaft 5206 can be flexible at the flexing portion 5232to position the first balloon against a vessel wall or ostium. Inaddition to or instead of fully occluding the vessel or ostium, theocclusion member 5204 can be configured in the expanded state to supportthe shaft 5206 within a renal artery or a renal ostium to providecontrolled repositioning of the cooling assembly 5202 within the renalartery or the renal ostium. For example, the cooling assembly 5202 canbe repositioned to cause therapeutically-effective, cryogenicrenal-nerve modulation at different portions of a renal artery or arenal ostium.

FIG. 53 illustrates a portion of a cryotherapeutic device 5300 similarto the cryotherapeutic device 5200 shown in FIGS. 53A-53B, but thedevice 5300 has additional distal cooling and different supply andcontrol configurations. The device 5300 includes a cooling assembly 5302and an occlusion member 5304 longitudinally spaced apart along anelongated shaft 5306 defining an exhaust passage. The shaft 5306 canhave a distal attachment point 5307 and a distal tip portion 5308defining a distal expansion chamber. The cooling assembly 5302 includesan applicator 5310 having a first balloon 5312 defining an expansionchamber, and the occlusion member 5304 includes a second balloon 5314defining an occlusion chamber fluidly separate from the exhaust passage.The device 5300 further includes a filler tube 5316 extending to thesecond balloon 5314 and a supply tube 5318 having a lateral branch 5320extending to the first balloon 5312 and an angled distal portion 5322extending to the distal tip portion 5308. The occlusion member 5304further includes a filler orifice 5324 through which a filler materialcan be supplied to the second balloon 5314. The cooling assembly 5302further includes a first supply orifice 5326 configured to directrefrigerant expansion into the first balloon 5312 and a second supplyorifice 5328 configured to direct refrigerant expansion into the distaltip portion 5308.

The device 5300 further includes an elongated control member 5330 and acontrol tube 5332. The control member 5330 can extend along the controltube 5332 and be attached to the distal attachment point 5307. Thedevice 5300 can be configured such that increasing or decreasing tensionof the control member 5330 can control deflection of the shaft 5306. Inaddition to or instead of fully occluding a vessel or ostium, theocclusion member 5304 can be configured in the expanded state to supportthe shaft 5306 within a renal artery or a renal ostium to providecontrolled repositioning of the cooling assembly 5302 within the renalartery or the renal ostium. For example, the cooling assembly 5302 canbe repositioned to cause therapeutically-effective, cryogenicrenal-nerve modulation at different portions of a renal artery or arenal ostium.

Alternative Cooling

Cooling assemblies configured in accordance with several embodiments ofthe present technology have a cooling mechanism in the deployed statethat does not involve evaporation of refrigerant. For example, suchembodiments can include cooling assemblies configured to circulateliquid or supercritical refrigerant at cryogenic temperatures to causeconvective and conductive cooling through a primary heat-transferportion of an applicator. In such applicators, the flow impedance of thesupply can be generally equal to the flow impedance of the exhaust. Forexample, the cross-sectional area of a supply lumen can be generallyequal to the cross-sectional area of an exhaust passage. In someembodiments, cryotherapeutic devices having cooling assembliesconfigured to circulate refrigerant without phase change can havefeatures to facilitate the supply of refrigerant to the coolingassemblies and/or the exhaust of refrigerant from the coolingassemblies. For example, a first pump can be included to increase thepressure of refrigerant flowing to a cooling assembly and/or a vacuumsource (e.g., a second pump) can be included to decrease the pressure ofrefrigerant flowing away from a cooling assembly. In addition to thefirst pump or alternatively, refrigerant can be supplied from apressurized source. Based on operational considerations, e.g.,refrigerant viscosity and flow impedances of supply, exhaust, andheat-transfer portions of a cryotherapeutic device, supply and exhaustpressures can be selected to cause different flow rates of refrigerant.The flow rate can be selected, for example, to correspond to aheat-transfer rate sufficient to cause therapeutically-effectivecryogenic renal nerve modulation.

FIG. 54 illustrates a portion of a cryotherapeutic device 5400 that canbe configured for convective heat transfer without refrigerantphase-change. The device 5400 includes a cooling assembly 5402 at adistal portion 5404 of an elongated shaft 5406 defining an exhaustpassage. The cooling assembly 5402 includes an applicator 5408 with aballoon 5410 that defines a circulation chamber. The device 5400 alsoincludes a supply tube 5412 extending along the length of the shaft 5406and into the balloon 5410, and the cooling assembly 5402 includes anorifice 5414 at the distal end of the supply tube 5412. In severalembodiments, the supply tube 5412 is relatively large and configured totransport liquid refrigerant, and the orifice 5414 is not configured tocause a pressure drop sufficient to evaporate a refrigerant. When thecooling assembly 5402 is in a deployed state, the balloon 5410 can beconfigured to be filled with refrigerant in at least a substantiallyliquid phase. The refrigerant can circulate from the supply tube 5412 tothe exhaust passage. FIG. 54 includes arrows 5416 indicating a directionof refrigerant flow through the balloon 5410. The refrigerant can be aliquid having a low freezing point (e.g., ethyl alcohol) and can betransported through the supply tube 5412 at a cryogenic temperature.Convective heat transfer between the refrigerant and the balloon 5410can cool a renal artery or a renal ostium to causetherapeutically-effective renal nerve modulation.

FIG. 55 illustrates a portion of a cryotherapeutic device 5500 that alsocan be configured for convective heat transfer without refrigerantphase-change. The device 5500 includes a cooling assembly 5502 at adistal portion 5504 of an elongated shaft 5506 including a shaftpartition 5508 dividing the shaft into a first longitudinal portion 5510defining supply lumen and a second longitudinal portion 5512 defining anexhaust passage. The cooling assembly 5502 includes an applicator 5514with a balloon 5516 including a balloon partition 5518 that defines aU-shaped chamber within the balloon 5516. The balloon 5516 can beconfigured to circulate liquid refrigerant from the first longitudinalportion 5510, through the U-shaped chamber, and into the secondlongitudinal portion 5512. FIG. 55 includes an arrow 5520 indicating adirection of refrigerant flow through the balloon 5516.

In several embodiments, a cooling assembly is configured to circulate asupercritical fluid (e.g., supercritical nitrogen or water).Supercritical fluids can provide significant cooling without phasechange, but typically must be maintained at relatively high pressures.Cooling assemblies configured to circulate supercritical fluids caninclude supply, heat-transfer, and exhaust structures having highpressure ratings. For example, such cooling assemblies can includenon-expandable applicators (e.g., having metal walls). Such applicatorscan be moveable during a treatment to contact different portions of arenal artery or a renal ostium.

Additional Embodiments

Features of the cryotherapeutic-device components described above andillustrated in FIGS. 1-5B and 12-55 can be modified to form additionalembodiments configured in accordance with the present technology. Forexample, the cryotherapeutic device 1700 illustrated in FIGS. 17A-17Band other cryotherapeutic devices described above and illustrated inFIGS. 1-5B and 12-55 without guide members can include guide membersthat extend near or through distal portions of balloons. Similarly, thecryotherapeutic devices described above and illustrated in FIGS. 1-5Band 12-55 can include control members configured to receive controlwires (e.g., pull wires). A control wire can be used, for example, tocontrol (e.g., deflect, angle, position, or steer) a cooling assembly,an applicator, or another cryotherapeutic-device component from outsidethe vasculature.

The cryotherapeutic-device components described above and illustrated inFIGS. 1-5B and 12-55 include balloons having a variety of features(e.g., shapes and compositions). In some cases, manufacturingconsiderations and other factors can cause certain features to be moreor less desirable. For example, certain materials can be more compatiblewith extrusion processes than with molding processes or vise versa.Similarly, some balloon shapes can be more readily formed using certainmanufacturing processes than using other manufacturing processes. Forexample, balloons having integral closed distal ends, in some cases, canbe difficult to form using extrusion. The balloons and balloon featuresin the cryotherapeutic-device components described above and illustratedin FIGS. 1-5B and 12-55 can be modified or interchanged according tosuch factors. For example, distal necks (e.g., sealed distal necks) canbe substituted for integral closed distal ends in the balloons describedabove and illustrated in FIGS. 1-5B and 12-55. This can be useful, forexample, to make the balloons more compatible with extrusionmanufacturing processes.

Features of the cryotherapeutic-device components described above alsocan be interchanged to form additional embodiments of the presenttechnology. For example, the inner balloon 1514 of the cooling assembly1502 illustrated in FIG. 15A can be incorporated into the coolingassembly 1902 shown in FIGS. 19A-19C. As another example, the firstsupply tube 1218 with the first angled distal portion 1222 of thecryotherapeutic device 1200 illustrated in FIG. 12 can be incorporatedinto the cooling assembly 1702 illustrated in FIGS. 17A-17B, with thefirst angled distal portion 1222 configured to direct expansion ofrefrigerant between the thermally-insulative members 1711.

Related Anatomy and Physiology

The Sympathetic Nervous System (SNS) is a branch of the autonomicnervous system along with the enteric nervous system and parasympatheticnervous system. It is always active at a basal level (called sympathetictone) and becomes more active during times of stress. Like other partsof the nervous system, the sympathetic nervous system operates through aseries of interconnected neurons. Sympathetic neurons are frequentlyconsidered part of the peripheral nervous system (PNS), although manylie within the central nervous system (CNS). Sympathetic neurons of thespinal cord (which is part of the CNS) communicate with peripheralsympathetic neurons via a series of sympathetic ganglia. Within theganglia, spinal cord sympathetic neurons join peripheral sympatheticneurons through synapses. Spinal cord sympathetic neurons are thereforecalled presynaptic (or preganglionic) neurons, while peripheralsympathetic neurons are called postsynaptic (or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation may elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine and epinephrine bind adrenergic receptorson peripheral tissues. Binding to adrenergic receptors causes a neuronaland hormonal response. The physiologic manifestations include pupildilation, increased heart rate, occasional vomiting, and increased bloodpressure. Increased sweating is also seen due to binding of cholinergicreceptors of the sweat glands.

The sympathetic nervous system is responsible for up- anddown-regulating many homeostatic mechanisms in living organisms. Fibersfrom the SNS innervate tissues in almost every organ system, providingat least some regulatory function to physiological features as diverseas pupil diameter, gut motility, and urinary output. This response isalso known as sympatho-adrenal response of the body, as thepreganglionic sympathetic fibers that end in the adrenal medulla (butalso all other sympathetic fibers) secrete acetylcholine, whichactivates the secretion of adrenaline (epinephrine) and to a lesserextent noradrenaline (norepinephrine). Therefore, this response thatacts primarily on the cardiovascular system is mediated directly viaimpulses transmitted through the sympathetic nervous system andindirectly via catecholamines secreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the sympatheticnervous system operated in early organisms to maintain survival as thesympathetic nervous system is responsible for priming the body foraction. One example of this priming is in the moments before waking, inwhich sympathetic outflow spontaneously increases in preparation foraction.

1. The Sympathetic Chain

As shown in FIG. 56, the SNS provides a network of nerves that allowsthe brain to communicate with the body. Sympathetic nerves originateinside the vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors which connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near theaortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons should travellong distances in the body, and, to accomplish this, many axons relaytheir message to a second cell through synaptic transmission. The endsof the axons link across a space, the synapse, to the dendrites of thesecond cell. The first cell (the presynaptic cell) sends aneurotransmitter across the synaptic cleft where it activates the secondcell (the postsynaptic cell). The message is then carried to the finaldestination.

In the SNS and other components of the peripheral nervous system, thesesynapses are made at sites called ganglia, discussed above. The cellthat sends its fiber is called a preganglionic cell, while the cellwhose fiber leaves the ganglion is called a postganglionic cell. Asmentioned previously, the preganglionic cells of the SNS are locatedbetween the first thoracic (T1) segment and third lumbar (L3) segmentsof the spinal cord. Postganglionic cells have their cell bodies in theganglia and send their axons to target organs or glands.

The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

2. Innervation of the Kidneys

As FIG. 57 shows, the kidney is innervated by the renal plexus RP, whichis intimately associated with the renal artery. The renal plexus RP isan autonomic plexus that surrounds the renal artery and is embeddedwithin the adventitia of the renal artery. The renal plexus RP extendsalong the renal artery until it arrives at the substance of the kidney.Fibers contributing to the renal plexus RP arise from the celiacganglion, the superior mesenteric ganglion, the aorticorenal ganglionand the aortic plexus. The renal plexus RP, also referred to as therenal nerve, is predominantly comprised of sympathetic components. Thereis no (or at least very minimal) parasympathetic innervation of thekidney.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord. Preganglionic axons pass through theparavertebral ganglia (they do not synapse) to become the lessersplanchnic nerve, the least splanchnic nerve, first lumbar splanchnicnerve, second lumbar splanchnic nerve, and travel to the celiacganglion, the superior mesenteric ganglion, and the aorticorenalganglion. Postganglionic neuronal cell bodies exit the celiac ganglion,the superior mesenteric ganglion, and the aorticorenal ganglion to therenal plexus RP and are distributed to the renal vasculature.

3. Renal Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages may trigger changes in different parts of the bodysimultaneously. For example, the sympathetic nervous system mayaccelerate heart rate; widen bronchial passages; decrease motility(movement) of the large intestine; constrict blood vessels; increaseperistalsis in the esophagus; cause pupil dilation, piloerection (goosebumps) and perspiration (sweating); and raise blood pressure. Afferentmessages carry signals from various organs and sensory receptors in thebody to other organs and, particularly, the brain.

Hypertension, heart failure and chronic kidney disease are a few of manydisease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. Pharmaceutical management of therenin-angiotensin-aldosterone system (RAAS) has been a longstanding, butsomewhat ineffective, approach for reducing over-activity of the SNS.

As mentioned above, the renal sympathetic nervous system has beenidentified as a major contributor to the complex pathophysiology ofhypertension, states of volume overload (such as heart failure), andprogressive renal disease, both experimentally and in humans. Studiesemploying radiotracer dilution methodology to measure overflow ofnorepinephrine from the kidneys to plasma revealed increased renalnorepinephrine (NE) spillover rates in patients with essentialhypertension, particularly so in young hypertensive subjects, which inconcert with increased NE spillover from the heart, is consistent withthe hemodynamic profile typically seen in early hypertension andcharacterized by an increased heart rate, cardiac output, andrenovascular resistance. It is now known that essential hypertension iscommonly neurogenic, often accompanied by pronounced sympathetic nervoussystem overactivity.

Activation of cardiorenal sympathetic nerve activity is even morepronounced in heart failure, as demonstrated by an exaggerated increaseof NE overflow from the heart and the kidneys to plasma in this patientgroup. In line with this notion is the recent demonstration of a strongnegative predictive value of renal sympathetic activation on all-causemortality and heart transplantation in patients with congestive heartfailure, which is independent of overall sympathetic activity,glomerular filtration rate, and left ventricular ejection fraction.These findings support the notion that treatment regimens that aredesigned to reduce renal sympathetic stimulation have the potential toimprove survival in patients with heart failure.

Both chronic and end stage renal disease are characterized by heightenedsympathetic nervous activation. In patients with end stage renaldisease, plasma levels of norepinephrine above the median have beendemonstrated to be predictive for both all-cause death and death fromcardiovascular disease. This is also true for patients suffering fromdiabetic or contrast nephropathy. There is compelling evidencesuggesting that sensory afferent signals originating from the diseasedkidneys are major contributors to initiating and sustaining elevatedcentral sympathetic outflow in this patient group; this facilitates theoccurrence of the well known adverse consequences of chronic sympatheticover activity, such as hypertension, left ventricular hypertrophy,ventricular arrhythmias, sudden cardiac death, insulin resistance,diabetes, and metabolic syndrome.

(i) Renal Sympathetic Efferent Activity

Sympathetic nerves to the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus and the renal tubules. Stimulation of therenal sympathetic nerves causes increased renin release, increasedsodium (Na+) reabsorption, and a reduction of renal blood flow. Thesecomponents of the neural regulation of renal function are considerablystimulated in disease states characterized by heightened sympathetictone and clearly contribute to the rise in blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome, which is renal dysfunction as a progressive complication ofchronic heart failure, with a clinical course that typically fluctuateswith the patient's clinical status and treatment. Pharmacologicstrategies to thwart the consequences of renal efferent sympatheticstimulation include centrally acting sympatholytic drugs, beta blockers(intended to reduce renin release), angiotensin converting enzymeinhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release)and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). However, the current pharmacologic strategies havesignificant limitations including limited efficacy, compliance issues,side effects and others.

(ii) Renal Sensory Afferent Nerve Activity

The kidneys communicate with integral structures in the central nervoussystem via renal sensory afferent nerves. Several forms of “renalinjury” may induce activation of sensory afferent signals. For example,renal ischemia, reduction in stroke volume or renal blood flow, or anabundance of adenosine enzyme may trigger activation of afferent neuralcommunication. As shown in FIGS. 58A and 58B, this afferentcommunication might be from the kidney to the brain or might be from onekidney to the other kidney (via the central nervous system). Theseafferent signals are centrally integrated and may result in increasedsympathetic outflow. This sympathetic drive is directed towards thekidneys, thereby activating the RAAS and inducing increased reninsecretion, sodium retention, volume retention and vasoconstriction.Central sympathetic over activity also impacts other organs and bodilystructures innervated by sympathetic nerves such as the heart and theperipheral vasculature, resulting in the described adverse effects ofsympathetic activation, several aspects of which also contribute to therise in blood pressure.

The physiology therefore suggests that (i) modulation of tissue withefferent sympathetic nerves will reduce inappropriate renin release,salt retention, and reduction of renal blood flow, and that (ii)modulation of tissue with afferent sensory nerves will reduce thesystemic contribution to hypertension and other disease statesassociated with increased central sympathetic tone through its directeffect on the posterior hypothalamus as well as the contralateralkidney. In addition to the central hypotensive effects of afferent renaldenervation, a desirable reduction of central sympathetic outflow tovarious other sympathetically innervated organs such as the heart andthe vasculature is anticipated.

B. Additional Clinical Benefits of Renal Denervation

As provided above, renal denervation is likely to be valuable in thetreatment of several clinical conditions characterized by increasedoverall and particularly renal sympathetic activity such ashypertension, metabolic syndrome, insulin resistance, diabetes, leftventricular hypertrophy, chronic end stage renal disease, inappropriatefluid retention in heart failure, cardio-renal syndrome, and suddendeath. Since the reduction of afferent neural signals contributes to thesystemic reduction of sympathetic tone/drive, renal denervation mightalso be useful in treating other conditions associated with systemicsympathetic hyperactivity. Accordingly, renal denervation may alsobenefit other organs and bodily structures innervated by sympatheticnerves, including those identified in FIG. 56. For example, aspreviously discussed, a reduction in central sympathetic drive mayreduce the insulin resistance that afflicts people with metabolicsyndrome and Type II diabetics. Additionally, patients with osteoporosisare also sympathetically activated and might also benefit from the downregulation of sympathetic drive that accompanies renal denervation.

C. Achieving Intravascular Access to the Renal Artery

In accordance with the present technology, neuromodulation of a leftand/or right renal plexus RP, which is intimately associated with a leftand/or right renal artery, may be achieved through intravascular access.As FIG. 59A shows, blood moved by contractions of the heart is conveyedfrom the left ventricle of the heart by the aorta. The aorta descendsthrough the thorax and branches into the left and right renal arteries.Below the renal arteries, the aorta bifurcates at the left and rightiliac arteries. The left and right iliac arteries descend, respectively,through the left and right legs and join the left and right femoralarteries.

As FIG. 59B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins. Above the renal veins, the inferior vena cava ascends to conveyblood into the right atrium of the heart. From the right atrium, theblood is pumped through the right ventricle into the lungs, where it isoxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter may beinserted percutaneously into the femoral artery through this accesssite, passed through the iliac artery and aorta, and placed into eitherthe left or right renal artery. This comprises an intravascular paththat offers minimally invasive access to a respective renal arteryand/or other renal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, brachial, or axillary artery maybe utilized in select cases. Catheters introduced via these accesspoints may be passed through the subclavian artery on the left side (orvia the subclavian and brachiocephalic arteries on the right side),through the aortic arch, down the descending aorta and into the renalarteries using standard angiographic technique.

D. Properties and Characteristics of the Renal Vasculature

Since neuromodulation of a left and/or right renal plexus RP may beachieved in accordance with the present technology through intravascularaccess, properties and characteristics of the renal vasculature mayimpose constraints upon and/or inform the design of apparatus, systems,and methods for achieving such renal neuromodulation. Some of theseproperties and characteristics may vary across the patient populationand/or within a specific patient across time, as well as in response todisease states, such as hypertension, chronic kidney disease, vasculardisease, end-stage renal disease, insulin resistance, diabetes,metabolic syndrome, etc. These properties and characteristics, asexplained herein, may have bearing on the efficacy of the procedure andthe specific design of the intravascular device. Properties of interestmay include, for example, material/mechanical, spatial, fluiddynamic/hemodynamic and/or thermodynamic properties.

As discussed previously, a catheter may be advanced percutaneously intoeither the left or right renal artery via a minimally invasiveintravascular path. However, minimally invasive renal arterial accessmay be challenging, for example, because as compared to some otherarteries that are toutinely accessed using catheters, the renal arteriesare often extremely tortuous, may be of relatively small diameter,and/or may be of relatively short length. Furthermore, renal arterialatherosclerosis is common in many patients, particularly those withcardiovascular disease. Renal arterial anatomy also may varysignificantly from patient to patient, which further complicatesminimally invasive access. Significant inter-patient variation may beseen, for example, in relative tortuosity, diameter, length, and/oratherosclerotic plaque burden, as well as in the take-off angle at whicha renal artery branches from the aorta. Apparatus, systems and methodsfor achieving renal neuromodulation via intravascular access shouldaccount for these and other aspects of renal arterial anatomy and itsvariation across the patient population when minimally invasivelyaccessing a renal artery.

In addition to complicating renal arterial access, specifics of therenal anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of a renalartery. When the neuromodulatory apparatus includes a cryotherapeuticdevice, consistent positioning, appropriate contact force applied by thecryotherapeutic device to the vessel wall, and adhesion between thecryo-applicator and the vessel wall are important for predictability.However, navigation is impeded by the tight space within a renal artery,as well as tortuosity of the artery. Furthermore, establishingconsistent contact is complicated by patient movement, respiration,and/or the cardiac cycle because these factors may cause significantmovement of the renal artery relative to the aorta, and the cardiaccycle may transiently distend the renal artery (i.e. cause the wall ofthe artery to pulse.

Even after accessing a renal artery and facilitating stable contactbetween neuromodulatory apparatus and a luminal surface of the artery,nerves in and around the adventia of the artery should be safelymodulated via the neuromodulatory apparatus. Effectively applyingthermal treatment from within a renal artery is non-trivial given thepotential clinical complications associated with such treatment. Forexample, the intima and media of the renal artery are highly vulnerableto thermal injury. As discussed in greater detail below, theintima-media thickness separating the vessel lumen from its adventitiameans that target renal nerves may be multiple millimeters distant fromthe luminal surface of the artery. Sufficient energy should be deliveredto or heat removed from the target renal nerves to modulate the targetrenal nerves without excessively cooling or heating the vessel wall tothe extent that the wall is frozen, desiccated, or otherwise potentiallyaffected to an undesirable extent. A potential clinical complicationassociated with excessive heating is thrombus formation from coagulatingblood flowing through the artery. Given that this thrombus may cause akidney infarct, thereby causing irreversible damage to the kidney,thermal treatment from within the renal artery should be appliedcarefully. Accordingly, the complex fluid mechanics and thermodynamicconditions present in the renal artery during treatment, particularlythose that may impact heat transfer dynamics at the treatment site, maybe important in applying energy (e.g., heating thermal energy) and/orremoving heat from the tissue (e.g., cooling thermal conditions) fromwithin the renal artery.

The neuromodulatory apparatus should also be configured to allow foradjustable positioning and repositioning of the energy delivery elementwithin the renal artery since location of treatment may also impactclinical efficacy. For example, it may be tempting to apply a fullcircumferential treatment from within the renal artery given that therenal nerves may be spaced circumferentially around a renal artery. Insome situations, full-circle lesion likely resulting from a continuouscircumferential treatment may be potentially related to renal arterystenosis. Therefore, the formation of more complex lesions along alongitudinal dimension of the renal artery via the cryotherapeuticdevices and/or repositioning of the neuromodulatory apparatus tomultiple treatment locations may be desirable. It should be noted,however, that a benefit of creating a circumferential ablation mayoutweigh the potential of renal artery stenosis or the risk may bemitigated with certain embodiments or in certain patients and creating acircumferential ablation could be a goal. Additionally, variablepositioning and repositioning of the neuromodulatory apparatus may proveto be useful in circumstances where the renal artery is particularlytortuous or where there are proximal branch vessels off the renal arterymain vessel, making treatment in certain locations challenging.Manipulation of a device in a renal artery should also considermechanical injury imposed by the device on the renal artery. Motion of adevice in an artery, for example by inserting, manipulating, negotiatingbends and so forth, may contribute to dissection, perforation, denudingintima, or disrupting the interior elastic lamina.

Blood flow through a renal artery may be temporarily occluded for ashort time with minimal or no complications. However, occlusion for asignificant amount of time should be avoided because to prevent injuryto the kidney such as ischemia. It could be beneficial to avoidocclusion all together or, if occlusion is beneficial to the embodiment,to limit the duration of occlusion, for example to 2-5 minutes.

Based on the above described challenges of (1) renal arteryintervention, (2) consistent and stable placement of the treatmentelement against the vessel wall, (3) effective application of treatmentacross the vessel wall, (4) positioning and potentially repositioningthe treatment apparatus to allow for multiple treatment locations, and(5) avoiding or limiting duration of blood flow occlusion, variousindependent and dependent properties of the renal vasculature that maybe of interest include, for example, (a) vessel diameter, vessel length,intima-media thickness, coefficient of friction, and tortuosity; (b)distensibility, stiffness and modulus of elasticity of the vessel wall;(c) peak systolic, end-diastolic blood flow velocity, as well as themean systolic-diastolic peak blood flow velocity, and mean/maxvolumetric blood flow rate; (d) specific heat capacity of blood and/orof the vessel wall, thermal conductivity of blood and/or of the vesselwall, and/or thermal convectivity of blood flow past a vessel walltreatment site and/or radiative heat transfer; (e) renal artery motionrelative to the aorta induced by respiration, patient movement, and/orblood flow pulsatility: and (f) as well as the take-off angle of a renalartery relative to the aorta. These properties will be discussed ingreater detail with respect to the renal arteries. However, dependent onthe apparatus, systems and methods utilized to achieve renalneuromodulation, such properties of the renal arteries, also may guideand/or constrain design characteristics.

As noted above, an apparatus positioned within a renal artery shouldconform to the geometry of the artery. Renal artery vessel diameter,D_(RA), typically is in a range of about 2-10 mm, with most of thepatient population having a D_(RA) of about 4 mm to about 8 mm and anaverage of about 6 mm. Renal artery vessel length, L_(RA), between itsostium at the aorta/renal artery juncture and its distal branchings,generally is in a range of about 5-70 mm, and a significant portion ofthe patient population is in a range of about 20-50 mm. Since the targetrenal plexus is embedded within the adventitia of the renal artery, thecomposite Intima-Media Thickness, IMT, (i.e., the radial outwarddistance from the artery's luminal surface to the adventitia containingtarget neural structures) also is notable and generally is in a range ofabout 0.5-2.5 mm, with an average of about 1.5 mm. Although a certaindepth of treatment is important to reach the target neural fibers, thetreatment should not be too deep (e.g., >5 mm from inner wall of therenal artery) to avoid non-target tissue and anatomical structures suchas the renal vein.

An additional property of the renal artery that may be of interest isthe degree of renal motion relative to the aorta induced by respirationand/or blood flow pulsatility. A patient's kidney, which is located atthe distal end of the renal artery, may move as much as 4″ craniallywith respiratory excursion. This may impart significant motion to therenal artery connecting the aorta and the kidney, thereby requiring fromthe neuromodulatory apparatus a unique balance of stiffness andflexibility to maintain contact between the cryo applicator or otherthermal treatment element and the vessel wall during cycles ofrespiration. Furthermore, the take-off angle between the renal arteryand the aorta may vary significantly between patients, and also may varydynamically within a patient, e.g., due to kidney motion. The take-offangle generally may be in a range of about 30°-135°.

The foregoing embodiments of cryotherapeutic devices are configured toaccurately position the cryo applicators in and/or near the renal arteryand/or renal ostium via a femoral approach, transradial approach, oranother suitable vascular approach. In any of the foregoing embodimentsdescribed above with reference to FIGS. 1-55, single balloons can beconfigured to be inflated to diameters of about 3 mm to about 8 mm, andmultiple-balloons can collectively be configured to be inflated todiameters of about 3 mm to about 8 mm, and in several embodiments 4 mmto 8 mm. Additionally, in any of the embodiments shown and describedabove with reference to FIGS. 1-55, the balloons can individually and/orcollectively have a length of about 8 mm to about 15 mm, and in severalembodiments 10 mm. For example, several specific embodiments of thedevices shown in FIGS. 1-55 can have a 10 mm long balloon that isconfigured to be inflated to a diameter of 4 mm to 8 mm. The shaft ofthe devices described above with reference to any of the embodimentsshown in FIGS. 1-55 can be sized to fit within a 6 Fr sheath, such as a4 Fr shaft size.

Conclusion

The above detailed descriptions of embodiments of the technology are notintended to be exhaustive or to limit the technology to the precise formdisclosed above. Although specific embodiments of, and examples for, thetechnology are described above for illustrative purposes, variousequivalent modifications are possible within the scope of thetechnology, as those skilled in the relevant art will recognize. Forexample, while steps are presented in a given order, alternativeembodiments may perform steps in a different order. The variousembodiments described herein may also be combined to provide furtherembodiments.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the technology. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the technology. Further, while advantagesassociated with certain embodiments of the technology have beendescribed in the context of those embodiments, other embodiments mayalso exhibit such advantages, and not all embodiments need necessarilyexhibit such advantages to fall within the scope of the technology.Accordingly, the disclosure and associated technology can encompassother embodiments not expressly shown or described herein.

We claim:
 1. A cryotherapeutic device, comprising: an elongated shafthaving a distal portion and a proximal portion; a cryogenic coolingassembly at the distal portion of the shaft; a supply lumen extendingalong a length of the shaft, the supply lumen being configured to carryrefrigerant distally toward the cooling assembly; a pre-cooling assemblyoperably connected to the supply lumen, the pre-cooling assemblyincluding— a first tubular region configured to contain refrigerant, asecond tubular region downstream from the first tubular region, and aflow separator disposed between the first and second tubular regions,the flow separator being configured to direct a first flow ofrefrigerant from the first tubular region into the supply lumen and todirect a second flow of refrigerant from the first tubular region intothe second tubular region; and a supply conduit defining a portion ofthe supply lumen extending through the second tubular region, wherein,in operation, the second flow of refrigerant expands within the secondtubular region in direct contact with the supply conduit, therebycooling the first flow of refrigerant while the first flow ofrefrigerant moves through the portion of the supply lumen extendingthrough the second tubular region.
 2. The cryotherapeutic device ofclaim 1 wherein: the supply conduit has an average outer diameter withinthe second tubular region; and the flow separator is a portion of thesupply conduit having an outer diameter greater than the average outerdiameter.
 3. The cryotherapeutic device of claim 1, wherein the shaft isconfigured to locate the cooling assembly at a treatment site within arenal artery of a human patient.
 4. The cryotherapeutic device of claim1, wherein the pre-cooling assembly includes: an exhaust port configuredto exhaust refrigerant from the second tubular region, and a valveoperably connected to the exhaust port, the valve being operable tocontrol a pressure of refrigerant within the second tubular region. 5.The cryotherapeutic device of claim 1, wherein the portion of the supplylumen extending through the second tubular region is at least partiallyserpentine.
 6. The cryotherapeutic device of claim 1, further comprisinga handle at the proximal portion of the shaft, wherein at least aportion of the pre-cooling assembly is within the handle.
 7. Thecryotherapeutic device of claim 1, wherein the first and second tubularregions form a continuous tube.
 8. The cryotherapeutic device of claim7, wherein the flow separator is slidingly disposed within the tube. 9.The cryotherapeutic device of claim 8 wherein the flow separator isfixed to an outer surface of the supply conduit.
 10. The cryotherapeuticdevice of claim 8, wherein the flow separator is configured to directthe second flow of refrigerant from the first tubular region into thesecond tubular region via a curved gap between the flow separator and aninner surface of the tube.
 11. The cryotherapeutic device of claim 10,wherein the curved gap is an annular gap.
 12. The cryotherapeutic deviceof claim 1, wherein the first and second flows of refrigerant arecoaxial.